Phosphodiesterase 4 inhibitors, including aminoindazole and aminobenzofuran analogs

ABSTRACT

PDE4 inhibition is achieved by novel compounds, e.g., aminoindazole and aminobenzofuran analogs. The compounds of the present invention are of Formulas I and II: 
                         
wherein R 1 , R 2 , R 3 , R 4 , R 7  and R 8  are as defined herein.

This application is a Divisional of application Ser. No. 10/622,117,filed Jul. 18, 2003, now U.S. Pat. No. 7,153,871, which claims benefitof 60/396,726, filed Jul. 19, 2002.

This application is related to application Ser. No. 10/051,309 and itsprovisional applications, Ser. No. 60/262,651, filed Jan. 22, 2001, Ser.No. 60/267,196, filed Feb. 8, 2001, and Ser. No. 60/306,140, filed Jul.14, 2001, their disclosures being hereby incorporated by reference intheir entirety.

FIELD OF THE INVENTION

The present invention relates generally to the field ofphosphodiesterase 4 (PDE4) enzyme inhibition. More specifically thisinvention relates to selective PDE4 inhibition by novel compounds, e.g.,aminoindazole and aminobenzofuran analogs, methods of preparing suchcompounds, compositions containing such compounds, and methods of usethereof.

BACKGROUND OF THE INVENTION

The cyclic nucleotide specific phosphodiesterases (PDEs) represent afamily of enzymes that catalyze the hydrolysis of various cyclicnucleoside monophosphates (including cAMP and cGMP). These cyclicnucleotides act as second messengers within cells, and as messengers,carry impulses from cell surface receptors having bound various hormonesand neurotransmitters. PDEs act to regulate the level of cyclicnucleotides within cells and maintain cyclic nucleotide homeostasis bydegrading such cyclic mononucleotides resulting in termination of theirmessenger role.

PDE enzymes can be grouped into eleven families according to theirspecificity toward hydrolysis of cAMP or cGMP, their sensitivity toregulation by calcium, calmodulin or cGMP, and their selectiveinhibition by various compounds. For example, PDE 1 is stimulated byCa²⁺/calmodulin. PDE 2 is cGMP-dependent, and is found in the heart andadrenals. PDE 3 is cGMP-dependent, and inhibition of this enzyme createspositive inotropic activity. PDE 4 is cAMP specific, and its inhibitioncauses airway relaxation, antiinflammatory and antidepressant activity.PDE 5 appears to be important in regulating cGMP content in vascularsmooth muscle, and therefore PDE 5 inhibitors may have cardiovascularactivity. Since the PDEs possess distinct biochemical properties, it islikely that they are subject to a variety of different forms ofregulation.

PDE4 is distinguished by various kinetic properties including lowMichaelis constant for cAMP and sensitivity to certain drugs. The PDE4enzyme family consists of four genes, which produce 4 isoforms of thePDE4 enzyme designated PDE4A, PDE4B, PDE4C, and PDE4D [See: Wang et al.,Expression, Purification, and Characterization of human cAMP-SpecificPhosphodiesterase (PDE4) Subtypes A, B, C, and D, Biochem. Biophys. Res.Comm., 234, 320-324 (1997)] In addition, various splice variants of eachPDE4 isoform have been identified.

PDE4 isoenzymes are localized in the cytosol of cells and areunassociated with any known membranous structures. PDE4 isoenzymesspecifically inactivate cAMP by catalyzing its hydrolysis to adenosine5′-monophosphate (AMP). Regulation of cAMP activity is important in manybiological processes, including inflammation and memory. Inhibitors ofPDE4 isoenzymes such as rolipram, piclamilast, CDP-840 and ariflo arepowerful antiinflammatory agents and therefore may be useful in treatingdiseases where inflammation is problematic such as asthma or arthritis.Further, rolipram improves the cognitive performance of rats and mice inlearning paradigms.

In addition to such compounds as rolipram, xanthine derivatives such aspentoxifylline, denbufylline, and theophylline inhibit PDE4 and havereceived considerable attention of late for their cognition enhancingeffects. cAMP and cGMP are second messengers that mediate cellularresponses to many different hormones and neurotransmitters. Thus,therapeutically significant effects may result from PDE inhibition andthe resulting increase in intracellular cAMP or cGMP in key cells, suchas those located in the nervous system and elsewhere in the body.

Rolipram, previously in development as an anti-depressant, selectivelyinhibits the PDE4 enzyme and has become a standard agent in theclassification of PDE enzyme subtypes. Early work in the PDE4 fieldfocused on depression and inflammation, and has subsequently beenextended to include indications such as dementia. [see “The PDE IVFamily Of Calcium-Phosphodiesterases Enzymes,” John A. Lowe, III, etal., Drugs of the Future 1992, 17(9):799-807 for a general review).Further clinical developments of rolipram and other first-generationPDE4 inhibitors were terminated due to the side effect profile of thesecompounds. The primary side effect in primates is emesis, while theprimary side effects in rodents are testicular degranulation, weakeningof vascular smooth muscle, psychotrophic effects, increased gastric acidsecretion and stomach erosion.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds, e.g., aminoindazoleand aminobenzofuran analogs, that inhibit PDE4 enzymes, and especiallyhave improved side effect profiles, e.g., are relatively non-emetic,(e.g., as compared to the previously discussed prior art compounds).Preferably, the compounds selectively inhibit PDE4 enzymes. Thecompounds of this invention at the same time facilitate entry intocells, especially cells of the nervous system.

Still further, the present invention provides methods for synthesizingcompounds with such activity and selectivity as well as methods of (andcorresponding pharmaceutical compositions for) treating a patient, e.g.,mammals, including humans, requiring PDE inhibition, especially PDE4inhibition, for a disease state that involves elevated intracellular PDE4 levels or decreased cAMP levels, e.g., involving neurologicalsyndromes, especially those states associated with memory impairment,most especially long term memory impairment, as where such memoryimpairment is due in part to catabolism of intracellular cAMP levels byPDE 4 enzymes, or where such memory impairment may be improved byeffectively inhibiting PDE4 enzyme activity.

In a preferred aspect, the compounds of the invention improve suchdiseases by inhibiting PDE4 enzymes at doses which do not induce emesis.

The present invention includes compounds of Formulas I and II:

wherein

-   R¹ is H,    -   alkyl having 1 to 8 carbon atoms, which is branched or        unbranched and which is unsubstituted or substituted one or more        times by halogen,    -   cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which        is unsubstituted or substituted one or more times by halogen,        hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy        having 1 to 4 carbon atoms, or combinations thereof (e.g.,        cyclopentyl), or    -   a heterocyclic group, which is saturated, partially saturated or        unsaturated, having 5 to 10 ring atoms in which at least 1 ring        atom is a N, O or S atom, which is unsubstituted or substituted        one or more times by halogen, alkyl, hydroxy, alkoxy,        alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy,        trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy        dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic        acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl        (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl,        alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or        combinations thereof (e.g., tetrahydrofuranyl, pyridyl, thienyl,        pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl,        thiazolyl, etc.),-   R² is H, or    -   alkyl having 1 to 4 carbon atoms, which is branched or        unbranched and which is unsubstituted or substituted one or more        times by halogen, cyano, and/or C₁₋₄-alkoxy (e.g., CH₃, C₂H₅,        CHF₂, CF₃, etc.), and one or more —CH₂CH₂— groups can be        replaced in each case by —CH═CH— or —C≡C—,-   R³ is H,    -   alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is        branched or unbranched and which is unsubstituted or substituted        one-or more times with halogen, cyano, C₁₋₄-alkoxy, or        combinations thereof (e.g., methyl, ethyl, propyl, etc.),    -   a partially unsaturated carbocycle-alkyl group wherein the        carbocyclic portion has 5 to 14 carbon atoms and the alkyl        portion which is branched or unbranched has 1 to 5 carbon atoms,        and which is unsubstituted or substituted in the carbocyclic        portion one or more times by halogen, alkyl, alkoxy, nitro,        cyano, oxo, or combinations thereof, and the alkyl portion is        optionally substituted by halogen, C₁₋₄-alkoxy, cyano or        combinations thereof (e.g., cyclohexenylmethyl, etc.),    -   arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion        has 6 to 14 carbon atoms and the alkyl portion, which is        branched or unbranched, has 1 to 5 carbon atoms, arylalkyl        radical is unsubstituted or substituted, in the aryl portion,        one or more times by halogen, trifluoromethyl, CF₃O, nitro,        amino, alkyl, alkoxy, alkylamino, dialkylarino and/or        substituted in the alkyl portion by halogen, cyano, or methyl        (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl,        methoxybenzyl, trfluoromethyl, benzyl, methylenedioxobenzyl,        etc.), or    -   heteroarylalkyl group, wherein the heteroaryl portion may be        partially or fully saturated and has 5 to 10 ring atoms in which        at least 1 ring atom is a N, O or S atom, the alkyl portion,        which is branched or unbranched, has 1 to 5 carbon atoms, the        heteroarylalkyl group is unsubstituted or substituted one or        more times in the heteroaryl portion by halogen, alkyl, alkoxy,        cyano, trifluoromethyl, CF₃O, nitro, oxo, amino, alkylamino,        dialkylamino, or combinations thereof and/or substituted in the        alkyl portion by halogen, cyano, or methyl or combinations        thereof (e.g., pyridylmethyl, pyridylpropyl,        methylpyridylmethyl, chloropyridylmethyl, dichloropyridylmethyl,        thienylmethyl, thiazolylmethyl, quinolinylmethyl,        isoquinolinylmethyl, piperidinylmethyl, furanylmethyl,        imidazolylmethyl, methylimidazolylmethyl, pyrrolylmethyl, etc.);-   R⁴ is H,    -   aryl having 6 to 14 carbon atoms and which is unsubstituted or        substituted one or more times by halogen, alkyl, alkenyl,        alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy,        ethylenedioxy, trifluoromethyl, OCF₃, amino, aminoalkyl,        aminoalkoxy dialkylamino, hydroxyalkyl (eg., hydroxymethyl),        hydroxamic acid, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl        (eg., 2-(2-tetrahydropyranyl)tetrazole-5-yl), hydroxyalkoxy,        carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl,        ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl,        alkylsulfonyl, phenoxy, trialkylsilyloxy (eg.        tert-butyldimethylsilyloxy), R⁵—L—, or combinations thereof        (e.g., substituted or unsubstituted phenyl, naphthyl, and        biphenyl, such as phenyl, methylphenyl, chlorophenyl,        fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl,        ethylphenyl, dichlorophenyl, carboxyphenyl,        ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl,        nitrophenyl, aminophenyl, etc.), or    -   heteroaryl having 5 to 10 ring atoms in which at least 1 ring        atom is a heteroatom, which is unsubstituted or substituted one        or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy,        nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino,        aminomethyl, aminoalkyl, aminoalkoxy dialk-ylamino, hydroxyalkyl        (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl,        hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g.,        tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio,        alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg.        tert-butyldimethylsilyloxy), R⁵—L—, or combinations thereof        (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl,        pyrimidinyl, imidazolyl, thiazolyl, etc.);-   R⁵ is H,    -   alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is        unsubstituted or substituted one or more times with halogen,        C₁₋₄-alkyl, C₁₋₄-alkoxy, oxo, or combinations thereof (e.g.,        methyl, ethyl, propyl, etc.),    -   alkylamino or dialkylamino wherein each alkyl portion has        independently 1 to 8, preferably 1 to 4 carbon atoms (e.g.,        dimethylamino, etc.),    -   a partially unsaturated carbocycle-alkyl group wherein the        carbocyclic portion has 5 to 14 carbon atoms and the alkyl        portion has 1 to 5 carbon atoms, which is unsubstituted or        substituted, preferably in the carbocyclic portion, one or more        times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or        combinations thereof (e.g., cyclohexenylmethyl, etc.),        cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which        is unsubstituted or substituted one or more times by halogen,        hydroxy, oxo, cyano, alkoxy, alkyl having 1 to 4 carbon atoms,        or combinations thereof (e.g., cyclopentyl),    -   cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms,        which is unsubstituted or substituted in the cycloalkyl portion        and/or the alkyl portion one or more times by halogen, oxo,        cyano, hydroxy, alkyl, alkoxy or combinations thereof (e.g.,        cyclopentylmethyl, cyclopropylmethyl, etc.),    -   aryl having 6 to 14 carbon atoms and which is unsubstituted or        substituted one or more times by halogen, alkyl, hydroxy,        alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy,        trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy        dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic        acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl        (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl,        alkylthio, alkylsulfinyl, alkylsulfonyl, (e.g., substituted or        unsubstituted phenyl and naphthyl, methylphenyl, chlorophenyl,        fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl,        ethylphenyl, dichlorophenyl, carboxyphenyl,        ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl,        nitrophenyl, aminophenyl, etc.),    -   arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion        has 6 to 14 carbon atoms and the alkyl portion, which is        branched or unbranched, has 1 to 5 carbon atoms, arylalkyl        radical is unsubstituted or substituted, in the aryl portion,        one or more times by halogen, trifluoromethyl, CF₃O, nitro,        amino, alkyl, alkoxy, amino, alkylamino, dialkylamino and/or        substituted in the alkyl portion by halogen, cyano, or methyl        (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl,        methoxybenzyl, trfluoromethyl, benzyl, methylenedioxobenzyl,        etc.),    -   a heterocyclic group, which is saturated, partially saturated or        unsaturated, having 5 to 10 ring atoms in which at least 1 ring        atom is a N, O or S atom, which is unsubstituted or substituted        one or more times by halogen, alkyl, hydroxy, alkoxy,        alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy,        trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy        dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxarnic        acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl        (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl,        alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or        combinations thereof (e.g., pyridyl, thienyl, pyrazinyl,        quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl,        etc.), or    -   a heterocycle-alkyl group, wherein the heterocyclic portion is        saturated, partially saturated or unsaturated, and has 5 to 10        ring atoms in which at least 1 ring atom is a N, O or S atom,        and the alkyl portion which is branched or unbranched and has 1        to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted        or substituted one or more times in the heterocyclic portion by        halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF₃O, nitro,        oxo, amino, alkylamino, dialkylamino, or combinations thereof        and/or substituted in the alkyl portion by halogen, cyano, or        methyl or combinations thereof (e.g., pyridylmethyl,        pyridylpropyl, methylpridylmethyl, etc.);-   L is a single bond or a divalent aliphatic radical having up to 8    carbon atoms wherein one or more —CH₂— groups are each optionally    replaced by —O—, —S—, —SO₂—, —SO—, NR₆—, —SO₂NH—, —NHSO₂—, —CO—,    —NR⁶CO—, —CONR⁶—, —NHCONH—, —OCONH, —NHCOO—, —SCONH—, —SCSNH—, or    —NHCSNH— (e.g., —O—, CH₂—, —CO—, —CO—O—, —O—CO—, —CO—NH—, —NH—CO—,    —CH₂CH₂CH₂—NH—CO—, —CH₂—CH₂—O—, —SO₂—NH—CH₂CH₂—O—, —O—CH₂CH₂—O—,    —CH₂—NH—CO—, —CO—NH—CH₂—, —SO₂—NH—, —CH₂—NH—SO₂—,    —CH₂CH₂CH₂—SO₂—NH—, —CONHSO₂—, etc.);-   R⁶ is H,    -   alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is        branched or unbranched and which is unsubstituted or substituted        one or more times with halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, oxo, or        combinations thereof (e.g., methyl, ethyl, propyl, etc.);-   R⁷ is alkoxy or alkylthio, in each case having 1 to 4 carbon atoms,    which is branched or unbranched and which is unsubstituted or    substituted one or more times by halogen (e.g., CH₃, CHF₂, CF₃,    etc.),-   R⁸ is —CO—C₁₋₄-alkyl which is branched or unbranched and which is    unsubstituted or substituted one or more times by halogen (e.g.,    CH₃, CHF₂, CF₃, etc.), or is

-   R⁹ is H or alkyl having 1 to 4 carbon atoms, which is branched or    unbranched, and which is unsubstituted or substituted one or more    times by halogen (e.g., CH₃, CHF₂, CF₃, etc.),-   R¹⁰ is alkyl having 1 to 6 carbon atoms, which is branched or    unbranched, and which is unsubstituted or substituted one or more    times by halogen (e.g., CH₃, CHF₂, CF₃, etc.),-   R¹¹ is alkyl having 1 to 6 carbon atoms, which is branched or    unbranched, and which is unsubstituted or substituted one or more    times by halogen (e.g., CH₃, CHF₂, CF₃, etc.),-   X and Y are each independently O or S, and-   A is alkylene having 2 to 7 carbon atoms which is unsubstituted or    substituted one or more times by halogen;

wherein in Formula I both of R³ and R⁴ are other than H and in FormulaII at least one of R³ and R⁴ is other than H; and

-   -   pharmaceutically acceptable salts thereof.

According to a further aspect of the invention there is provided a genusof novel compounds according to the formulas III and IV:

wherein R¹, R², R³, R⁴, R⁷ and R⁸ are as defined above. The compounds ofthis subgenus of Formulae I and II not only have PDE4 inhibitoryactivity, but also are useful as intermediates for preparing compoundsof Formula II in which R³ and R⁴ are both other than H.

In addition, preferred compounds of Formulas I and II are those ofsubformulas V and VI

wherein R¹, R², R⁴, R⁷ and R⁸ are as defined in Formulas I and II andone of B, D and E is N and the others are C. Preferably, D is N. Also,R⁴ is preferably pyridyl or phenyl which in each case is substituted orunsubstituted.

In accordance with a further aspect of the invention the compounds offormulas I and II are selected from the following compounds:

-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-(4-pyridylmethyl)]aminobenzofuran,-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-(3-pyridylmethyl)]aminobenzofuran,-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-phenyl-N-(4-pyridylmethyl)]aminobenzofuran,-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-(3-cyanophenyl)-N-(3-pyridylmethyl)]aminobenzofuran,-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-phenyl-N-(3-pyridylmethyl)]aminobenzoifuran,-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-(3-cyanophenyl)-N-(4-pyridylmethyl)]aminobenzofuran,-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-(4-acetylphenyl)-N-(3-pyridylmethyl)]aminobenzofuran,-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-(4-carboxyphenyl)-N-(3-pyridylmethyl)]aminobenzofuran,-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-(4-(2H-tetrazol-5-yl)phenyl)-N-(3-pyridylmethyl]aminobenzofuran,-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-(4-carboxy-3-chlorophenyl)-N-(3-pyridylmethyl)]aminobenzofuran,-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-(3-carboxy-5-fluorophenyl)-N-(3-pyridylmethyl)]aminobenzofuran,-   1-Cyclopentyl-6-[N-(3-(1,1-dimethylethoxycarbonyl)phenyl)-N-(3-pyridylmethyl)]-1H-aminoindazole,-   2-Acetyl-7-methoxy-4-(N-(4-cyanophenyl)-N-(3-pyridylnethyl))aminobenzofuran,-   2-Acetyl-7-methoxy-4-(N-phenyl-N-(4-pyridylmethyl))aminobenzofuran,-   1-Cyclopentyl-6-(N-phenyl-N-(3-pyridylnethyl))aminoindazole,-   1-Cyclopentyl-6-(N-(3-carboxyphenyl)-N-(3-pyridylmethyl))aminoindazole,-   2-Acetyl-7-methoxy-4-(N-(3-carboxyphenyl)-N-(3-pyridylmethyl))aminobenzofuran,-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-(N-(4-cyanophenyl)-N-(3-pyridylmethyl))-aminobenzofuran,-   2-Acetyl-7-methoxy-4-(N-(3-cyanophenyl)-N-(3-pyridylmethyl))aminobenzofuran,-   2-Acetyl-7-methoxy-4-(N-phenyl-N-(3-pyridylmethyl))aminobenzofuran,-   2-Acetyl-7-methoxy-4-(N-(3-cyanophenyl)-N-(4-pyridylmethyl))aminobenzofuran,-   2-Acetyl-7-methoxy-4-(N-(4-acetylphenyl)-N-(3-pyridylmethyl))aminobenzofaran,-   2-Acetyl-7-methoxy-4-[N-(4-carboxyphenyl)-N-(3-pyridylmethyl)]aminobenzofuran,-   2-Acetyl-7-methoxy-4-[N-(4-(2H-tetrazol-5-yl)phenyl)-N-(3-pyridylmethyl]aminobenzofuran,-   2-Acetyl-7-methoxy-4-[N-(4-carboxy-3-chlorophenyl)-N-(3-pyridylmethyl)]aminobenzofuran,-   2-Acetyl-7-methoxy-4-[N-(3-carboxy-5-fluorophenyl)-N-(3-pyridylmethyl)]aminobenzofuran,-   6-Amino-1-cyclopentyl-3-ethyl-6-[N-3-(1,1-dimethylethoxycarbonyl)phenyl]-N-(3-pynrdylmethyl)amino-1H-indazole,-   1-Cyclopentyl-3-ethyl-6-[N-(3-carboxyphenyl)-N-(3-pyridylmethyl)]amino-1H-indazole,-   2-Acetyl-7-methoxy-N-(4-phenylsulfonylaminocarbonylphenyl)-N-(3-pyridyliethyl)-4-aminobenzofuran,    and    pharmaceutically acceptable salts thereof,

wherein optically active compounds can be in the form of their separateenantiomers or mixtures thereof, including racemic mixtures.

The compounds of the present invention are effective in inhibiting, ormodulating the activity of PDE4 in animals, e.g., mammals, especiallyhumans. These compounds exhibit neurological activity, especially wheresuch activity affects cognition, including long term memory. Thesecompounds will also be effective in treating diseases where decreasedcAMP levels are involved. This includes but is not limited-toinflammatory diseases. These compounds may also function asantidepressants, or be useful in treating cognitive and negativesymptoms of schizophrenia.

Assays for determining PDE inhibiting activity as well as selectivity ofPDE 4 inhibiting activity and selectivity of inhibiting PDE 4 isoenzymesare known within the art. See, e.g., U.S. Pat. No. 6,136,821, thedisclosure of which is incorporated herein by reference.

According to a further aspect of the invention there are providedcompounds useful as intermediates for the production of the PDE4inhibitors described herein (e.g., PDE4 inhibitors of Formulas I and II)and/or useful for the synthesis of radio-labeled analogs of the PDE4inhibitors with in this application.

Thus, there are provided intermediate compounds which correspond tocompounds of Formulas I and II, wherein R², R³, R⁴ and R⁸ are aspreviously defined for Formulas I and II, but R¹ or R⁷ is H,tert-butyldimethylsilyl-, or a suitable phenolic or indazolyl protectinggroup. Suitable protecting groups are described, for example, in Greene,T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, 3^(rd)Edition, John Wiley & Sons, 1999, pp. 246-293. These intermediates arealso useful for the synthesis of radio-labeled compounds, such as whereR⁷ is ³H₃CO—, ²H₃CO—, ¹⁴CH₃— or ¹¹CH₃—, for example by removing theprotecting group and reacting the resultant compound in which R¹ or R⁷is H with suitable radio-labeled reagents. Such radio-labeled compoundsare useful for determining compound tissue distribution in animals, inPET imaging studies, and for in vivo, ex vivo, and in vitro bindingstudies.

As previously described, compounds according to formula III, wherein R⁴,R⁷ and R⁸ are as previously described are useful intermediates for theproduction of compounds according to formula II where in R³ is otherthan H.

Also, as previously described, compounds according to formula IV,wherein R³, R⁷ and R⁸ are as previously described are usefulintermediates for the production of compounds according to formula IIwhere in R⁴ is other than H.

Halogen herein refers to F, Cl, Br, and I. Preferred halogens are F andCl.

Alkyl, as a group or substituent per se or as part of a group orsubstituent (e.g., alkylamino, trialkylsilyloxy, aminoalkyl,hydroxyalkyl), means a straight-chain or branched-chain aliphatichydrocarbon radical having 1 to 12 carbon atoms, preferably 1 to 8carbon atoms, especially 1 to 4 carbon atoms. Suitable alkyl groupsinclude methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl,pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. Otherexamples of suitable alkyl groups include 1-, 2- or 3-methylbutyl, 1,1-,1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, 1-, 2-, 3- or 4-methylpentyl,1,1-, 1,2-, 1,3-, 2,2-, 3,3-dimethylbutyl, 1- or 2-ethylbutyl,ethylmethylpropyl, trimethylpropyl, methylhexyl, dimethylpentyl,ethylpentyl, ethylmethylbutyl, dimethylbutyl, and the like.

Substituted alkyl groups are alkyl groups as described above which aresubstituted in one or more positions by halogens, oxo, hydroxyl,C₁₋₄-alkoxy and/or cyano. Halogens are preferred substituents,especially F and Cl.

Alkoxy means alkyl-O— groups and alkoxyalkoxy means alkyl-O-alkyl-O—groups in which the alkyl portions are in accordance with the previousdiscussion. Suitable alkoxy and alkoxyalkoxy groups include methoxy,ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy methoxymethoxyethoxymethoxy, propoxymethoxy, and methoxyethoxy. Preferred alkoxygroups are methoxy and ethoxy. Similarly, alkoxycarbonyl means alkyl—O—CO— in which the alkyl portion is in accordance with the previousdiscussion. Examples include methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, and tert-butoxycarbonyl.

Cycloalkyl means a monocyclic, bicyclic or tricyclic nonaromaticsaturated hydrocarbon radical having 3 to 10 carbon atoms, preferably 3to 8 carbon atoms, especially 3 to 6 carbon atoms. Suitable cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, norbornyl, 1-decalin, adamant-1-yl, andadamant-2-yl. Other suitable cycloalkyl groups include spiropentyl,bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, spiro[2.4]heptyl,spiro[2.5]octyl, bicyclo[5.1.0]octyl, spiro[2.6]nonyl,bicyclo[2.2.0]hexyl, spiro[3.3]heptyl, bicyclo[4.2.0]octyl, andspiro[3.5]nonyl. Preferred cycloalklyl groups are cyclopropyl,cyclopentyl and cyclohexyl. The cycloalkyl group can be substituted, forexample, substituted by halogens and/or alkyl groups.

Cycloalkylalkyl refers to cycloalkyl-alkyl radicals in which thecycloalkyl and alkyl portions are in accordance with previousdiscussions. Suitable examples include cyclopropyhnethyl andcyclopentylmethyl.

Aryl, as a group or substituent per se or as part of a group orsubstituent, refers to an aromatic carbocyclic radical containing 6 to14 carbon atoms, preferably 6 to 12 carbon atoms, especially 6 to 10carbon atoms. Suitable aryl groups include phenyl, naphthyl andbiphenyl. Substituted aryl groups include the above-described arylgroups which are substituted one or more times by, for example, halogen,alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino,alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano,acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, andphenoxy.

Arylalkyl refers to an aryl-alkyl-radical in which the aryl and alkylportions are in accordance with the previous descriptions. Suitableexamples include benzyl, 1-phenethyl, 2-phenethyl, phenpropyl,phenbutyl, phenpentyl, and napthylmethyl.

Heteroaryl refers to an aromatic heterocyclic group having one or tworings and a total number of 5 to 10 ring atoms wherein at least one ofthe ring atoms is a heteroatom. Preferably, the heteroaryl groupcontains 1 to 3, especially 1 or 2, hetero-ring atoms which are selectedfrom N, O and S. Suitable heteroaryl groups include furyl, thienyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, dithialyl,oxathialyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,oxatriazolyl, dioxazolyl, oxathiazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazinyl, isoxazinyl,oxathiazinyl, oxadiazinyl, benzofuranyl, isobenzofuranyl,thionaphthenyl, isothionaphthenyl, indolyl, isoindolyl, indazolyl,benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzisothiazolyl, purinyl,benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl,naphthyridinyl, and benzoxazinyl, e.g., 2-thienyl, 3-thienyl, 2-, 3- or4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl and 1-, 3-, 4-, 5-,6-, 7-or 8-isoquinolinyl.

Substituted heteroaryl refers to the heteroaryl groups described abovewhich are substitued in one or more places by, for example, halogen,aryl, alkyl, alkoxy, carboxy, methylene, cyano, trifluoromethyl, nitro,oxo, amino, alkylamino, and dialkylamino.

Heterocycles include heteroaryl groups as described above as well asnon-aromatic cyclic groups containing at least one hetero-ring atom,preferably selected from N, S and O, for example, tetrahydrofuranyl,piperidinyl, and pyrrolidinyl.

Heterocycle-alkyl refers to a heterocycle-alkyl-group wherein theheterocyclic and alkyl portions are in accordance with the previousdiscussions. Suitable examples are pyridylmethyl, thienylmethyl,pyrimidinylmethyl, pyrazinylmethyl, and isoquinolinylmethyl.

Partially unsaturated carbocyclic structures are non-aromatic monocyclicor bicyclic structures containing 5 to 14 carbon atoms, preferably 6 to10 carbon atoms, wherein the ring structure(s) contains at least one C═Cbond. Suitable examples are cyclopentenyl, cyclohexenyl,cyclohexadienyl, tetrahydronaphthenyl and indan-2-yl.

Alkenyl refers to straight-chain or branched-chain aliphatic radicalscontaining 2 to 12 carbon atoms in which one or more —CH₂—CH₂—structures are each replaced by —CH═CH—. Suitable alkenyl groups areethenyl, 1-propenyl, 2-methylethenyl, 1-butene, 2-butene, 1-pentenyl,and 2-pentenyl.

Alkynyl refers to straight-chain or branched-chain aliphatic radicalscontaining 2 to 12 carbon atoms in which one or more —CH₂—CH₂—structures are each replaced by —C═C—. Suitable alkynyl groups areethynyl, propynyl, 1-butynyl, and 2-butynyl.

Acyl refers to alkanoyl radicals having 1 to 13 carbon atoms in whichthe alkyl portion can be substituted by halogen, alkyl, aryl and/oralkoxy, or aroyl radicals having 7 to 15 carbon atoms in which the arylportion can be substituted by, for example, halogen, alkyl and/oralkoxy. Suitable acyl groups include fonnyl, acetyl, propionyl, butanoyland benzoyl.

Substituted radicals preferably have 1 to 3 substituents, especially 1to 2 substituents.

In the compounds of Formula I, R¹ can be an alkyl group havingpreferably 2 to 4 carbon atoms which is optionally substituted byhalogen, preferably fluorine or chlorine.

R¹ can also preferably be cycloalkyl, particularly cyclopentyl orcyclohexyl.

R² is preferably H or alkyl having 1 to 4 carbon atoms, especially C₂H₅.

R³ is preferably hydrogen, alkyl having 1 to 4 carbon atoms (e.g.,methyl, ethyl, n-propyl, or n-butyl), arylalkyl (e.g., substituted orunsubstituted benzyl, phenethyl, and phenpropyl), or a heteroarylalkylgroup (e.g., substituted or unsubstituted pyridylmethyl, furanylmethyl,thienylmethyl, pyrrolylmethyl, pyrimidinylmethyl, thiazolylmethyl,isoquinolinylmethyl and quinolinylmethyl). Preferred substituents foraryl and heteroaryl portions of R³ are F, Cl, CH₃, C₂H₅, OCH₃ and CN. Inparticular, R³ is preferably pyridylmethyl.

R⁴ is preferably aryl, or heteroaryl, especially phenyl, naphthyl,biphenyl, furanyl, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, andisoquinolinyl, which in each case is unsubstituted or is substituted oneor more times. Preferred substituents are OH, F, Cl, CF₃, alkyl (such asmethyl or ethyl), alkoxy (such as methoxy and ethoxy), CN, vinyl, CH₂OH,CONHOH, CONH₂, methylenedioxy, COOH, and combinations thereof Forexample, R⁴ can be phenyl substituted by halogen, COOH and/or CN.

In addition, when R⁴ is aryl, especially, phenyl, preferred substituentsinclude R⁵—L—, e.g., R⁵—, R⁵—O—, R⁵—CO—, R⁵—NH—CO—, R⁵—SO₂—NH—,R⁵—SO₂—NH-alkylene-O—, NH₂-alkyl-NH—CO—, R⁵-alkylene-NH—CO—,alkyl-CO—NH-alkyl- as well as methyl, ethyl, Cl, F, CN, OCH₃, CF₃,amino, nitro, HOCH₂ and COOH.

When R⁴ is aryl substituted by R⁵—SO₂—NH— it is preferably a substitutedphenyl group and R⁵ is preferably methyl, ethyl, propyl or phenyl.

When R⁴ is aryl substituted by R⁵—SO₂—NH-alkylene-O— it is preferably asubstituted phenyl. In such cases, R⁵ is preferably methyl, ethyl,propyl or phenyl and alkylene is preferably —CH₂—, —CH₂CH₂— or—CH₂CH₂CH₂—.

When R⁴ is aryl substituted by R⁵—L— it is preferably substitutedphenyl. In such cases, preferred R⁵ groups include phenyl, tetrazolyl,oxazinyl, piperazinyl, rnethylpiperazinyl, pyridyl, methylpyridyl,pyrrolihyl, methylpyrrolinyl, piperadinyl, or methylpiperadinyl, and Lis preferably a single bond, —O—, —CO—, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂—O—, —CH₂CH₂—O—, —CH₂CH₂CH₂—O—, —CH₂—NH—CH₂CH₂—O—, —CO—NH—, —NH—CO—,or —CONHSO₂—.

R⁷ is preferably alkoxy having 1 to 4 carbon atoms, which is branched orunbranched and which is unsubstituted or substituted one or more timesby halogen, e.g., CH₃ or C₂H₅.

R⁸ is preferably —CO—C₁₋₄-alkyl, e.g., —COCH₃.

R⁹ is preferably —CH₃.

X and Y are preferably both O or S, especially O.

A is preferably —CH₂CH₂—.

In addition, preferred PDE4 inhibitors in accordance with the inventionare compounds described by subformulas Ia to IIe which correspond toformulas I and II but exhibit the following preferred groups:

-   Ia R³ is arylalkyl or heteroarylalkyl, in each case substituted or    unsubstituted; and    -   R⁴ is H or is aryl or heteroaryl, in each case substituted or        unsubstituted.-   Ib R¹ is cycloalkyl; and    -   R² is H or C₂H₅.-   Ic R¹ is cycloalkyl;    -   R² is H or C₂H₅;    -   R³ is arylalkyl or heteroarylalkyl, in each case substituted or        unsubstituted; and    -   R⁴ is H or is aryl or heteroaryl, in each case substituted or        unsubstituted.-   Id R¹ is cyclopentyl;    -   R² is H or C₂H₅;    -   R³ is arylalkyl or heteroarylalkyl, in each case substituted or        unsubstituted; and    -   R⁴ is H or is aryl or heteroaryl, in each case substituted or        unsubstituted.-   Ie R¹ is cyclopentyl;    -   R² is H or C₂H₅;    -   R³ is pyridyl which is substituted or unsubstituted; and    -   R⁴ is H or is aryl or heteroaryl, in each case substituted or        unsubstituted.-   If R¹ is cyclopentyl;    -   R² is H or C₂H₅;    -   R³ is pyridyl which is substituted or unsubstituted; and    -   R⁴ is phenyl which is substituted or unsubstituted.-   IIa R³ is arylalkyl or heteroarylalkyl, in each case substituted or    unsubstituted; and    -   R⁴ is H or is aryl or heteroaryl, in each case substituted or        unsubstituted.-   IIb R⁷ is alkoxy having 1 to 4 carbon atoms;    -   R⁸ is COCH₃ or

-   -   R⁹ is —CH₃;    -   X and Y are both O or S; and    -   A is —CH₂CH₂—.

-   IIc R³ is arylallcyl or heteroarylalkyl, in each case substituted or    unsubstituted; and    -   R⁴ is H or is aryl or heteroaryl, in each case substituted or        unsubstituted;    -   R⁷ is alkoxy having 1 to 4 carbon atoms;    -   R⁸ is COCH₃ or

-   -   R⁹ is —CH₃;    -   X and Y are both O or S; and    -   A is —CH₂CH₂—.

-   IId R³ is pyridyl which is substituted or unsubstituted;    -   R⁴ is H or is aryl or heteroaryl, in each case substituted or        unsubstituted;    -   R⁷ is alkoxy having 1 to 4 carbon atoms;    -   R⁸ is COCH₃ or

-   -   R⁹ is —CH₃;    -   X and Y are both O or S; and    -   A is —CH₂CH₂—.

-   IIe R³ is pyridyl which is substituted or unsubstituted;    -   R⁴ is phenyl which is substituted or unsubstituted;    -   R⁷ is alkoxy having 1 to 4 carbon atoms;    -   R⁸ is COCH₃ or

-   -   R⁹is —CH₃;    -   X and Y are both O or S; and    -   A is —CH₂CH₂—.

Preferred aspects include pharmaceutical compositions comprising acompound of this invention and a pharmaceutically acceptable carrierand, optionally, another active agent as discussed below; a method ofinhibiting a PDE4 enzyme, especially an isoenzyme, e.g., as determinedby a conventional assay or one described herein, either in vitro or invivo (in an animal, e.g., in an animal model, or in a mammal or in ahuman); a method of treating neurological syndrome, e.g., loss ofmemory, especially long-term memory, cognitive impairment or decline,memory impairment, etc. a method of treating a disease state modulatedby PDE4 activity, in a mammal, e.g., a human, e.g., those mentionedherein.

The compounds of the present invention may be prepared conventionally.All starting materials are known or can be conventionally prepared fromknown starting materials. Some of the processes which can be used aredescribed below.

Starting material 6-amino-1-cyclopentyl-3-ethylindazole can besynthesized from the corresponding6-carboxy-1-cyclopentyl-3-ethylindazole by a Curtius rearrangement. Thestarting 6-carboxy-1-cyclopentyl-3-ethylindazole can be prepared bymethods common in the art (see, e.g., WO 098/09961). Alternatively,starting 6-amino-1-cyclopentyl-3-ethylindazoles can be synthesized byamination of 6-halo-1-cycloalkyl-3-ethylindazole or reduction of6-nitro-1-cycloalkyl-3-ethylindazole. The indazole scaffold can beprepared by several methods common to the art, such as by reaction ofcycloalkylhydrazine with 2,4-difluoropropiophenone.

Starting benzofurans are either commercially available or can besynthesized according literature methods by intramolecular aldolcondensation of appropriately substituted beta-ketoethers ofsalicylaldehydes. (see Strategies for Organic Drug Synthesis and Design,Daniel Lednicer, Ed., 1998, John Wiley and Sons, Inc. Chapter 10 pp.286-289). Nitration of 2-acetyl-7-methoxybenzofuran with nitric acid inacetic anhydride provides 2-acetyl-7-methoxy-4-nitrobenzofuran. (in theabove scheme, DPA patent refers to U.S. patent application Ser. No.10/051,309).

Protection of the carbonyl group with a suitable base stable protectinggroup such as a dioxane or dioxolane provides the desired starting4-nitrobenzofurans. See also WO 99/40085 and WO 99/37640.

One of ordinary skill in the art will recognize that some of thecompounds of Formulas I and II can exist in different geometricalisomeric forms. In addition, some of the compounds of the presentinvention possess one or more asymmetric carbon atoms and are thuscapable of existing in the form of optical isomers, as well as in theform of racemic or nonracernic mixtures thereof, and in the form ofdiastereomers and diastereomeric mixtures inter alia. All of thesecompounds, including cis isomers, trans isomers, diastereomic mixtures,racemates, nonracemic mixtures of enantiomers, and substantially pureand pure enantiomers, are within the scope of the present invention.Substantially pure enantiomers contain no more than 5% w/w of thecorresponding opposite enantiomer, preferably no more than 2%, mostpreferably no more than 1%.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, dibenzoyltartaric,ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomerscan be separated into their individual diastereomers on the basis oftheir physical and/or chemical differences by methods known to thoseskilled in the art, for example, by chromatography or fractionalcrystallization. The optically active bases or acids are then liberatedfrom the separated diastereomeric salts. A different process forseparation of optical isomers involves the use of chiral chromatography(e.g., chiral HPLC columns), with or without conventional derivation,optimally chosen to maximize the separation of the enantiomers. Suitablechiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD andChiracel OJ among many others, all routinely selectable. Enzymaticseparations, with or without derivitization, are also useful. Theoptically active compounds of Formulae I and II can likewise be obtainedby chiral syntheses utilizing optically active starting materials.

In addition, one of ordinary skill in the art will recognize that thecompounds can be used in different enriched isotopic forms, e.g.,enriched in the content of ²H, ³H, ¹¹C and/or ¹⁴C.

The present invention also relates to useful forms of the compounds asdisclosed herein, such as pharmaceutically acceptable salts and prodrugsof all the compounds of the present invention. Pharmaceuticallyacceptable salts include those obtained by reacting the main compound,functioning as a base, with an inorganic or organic acid to form a salt,for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid,methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid,succinic acid and citric acid. Pharmaceutically acceptable salts alsoinclude those in which the main compound functions as an acid and isreacted with an appropriate base to form, e.g., sodium, potassium,calcium, rnangnesium, ammonium, and choline salts. Those skilled in theart will further recognize that acid addition salts of the claimedcompounds may be prepared by reaction of the compounds with theappropriate inorganic or organic acid via any of a number of knownmethods. Alternatively, alkali and alkaline earth metal salts areprepared by reacting the compounds of the invention with the appropriatebase via a variety of known methods.

The following are further examples of acid salts that can be obtained byreaction with inorganic or organic acids: acetates, adipates, alginates,citrates, aspartates, benzoates, benzenesulfonates, bisulfates,butyrates, camphorates, digluconates, cyclopentanepropionates,dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates,heniisulfates, heptanoates, hexanoates, fumarates, hydrobrorides,hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates,methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates,palmoates, pectinates, persulfates, 3-phenylpropionates, picrates,pivalates, propionates, succinates, tartrates, thiocyanates, tosylates,mesylates and undecanoates.

Preferably, the salts formed are pharmaceutically acceptable foradministration to mammals. However, pharmaceutically unacceptable saltsof the compounds are suitable as intermediates, for example, forisolating the compound as a salt and then converting the salt back tothe free base compound by treatment with an alkaline reagent. The freebase can then, if desired, be converted to a pharmaceutically acceptableacid addition salt.

The compounds of the invention can be administered alone or as an activeingredient of a formulation. Thus, the present invention also includespharmaceutical compositions of compounds of Formulas I or II containing,for example, one or more pharmaceutically acceptable carriers.

Numerous standard references are available that describe procedures forpreparing various formulations suitable for administering the compoundsaccording to the invention. Examples of potential formulations andpreparations are contained, for example, in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (currentedition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman andSchwartz, editors) current edition, published by Marcel Dekker, Inc., aswell as Remington's Pharmaceutical Sciences (Arthur Osol, editor),1553-1593 (current edition).

In view of their high. degree of PDE4 inhibition, the compounds of thepresent invention can be administered to anyone requiring or desiringPDE4 inhibition, and/or enhancement of cognition. Administration may beaccomplished according to patient needs, for example, orally, nasally,parenterally (subcutaneously, intravenously, intramuscularly,intrasternally and by infusion), by inhalation, rectally, vaginally,topically, locally, transdermally, and by ocular administration.

Various solid oral dosage forms can be used for administering compoundsof the invention including such solid forms as tablets, gelcaps,capsules, caplets, granules, lozenges and bulk powders. The compounds ofthe present invention can be administered alone or combined with variouspharmaceutically acceptable carriers, diluents (such as sucrose,mannitol, lactose, starches) and excipients known in the art, includingbut not limited to suspending agents, solubilizers, buffering agents,binders, disintegrants, preservatives, colorants, flavorants, lubricantsand the like. Time release capsules, tablets and gels are alsoadvantageous in administering the compounds of the present invention.

Various liquid oral dosage forms can also be used for administeringcompounds of the invention, including aqueous and non-aqueous solutions,emulsions, suspensions, syrups, and elixirs. Such dosage forms can alsocontain suitable inert diluents known in the art such as water andsuitable excipients known in the art such as preservatives, wettingagents, sweeteners, flavorants, as well as agents for emulsifying and/orsuspending the compounds of the invention. The compounds of the presentinvention may be injected, for example, intravenously, in the form of anisotonic sterile solution. Other preparations are also possible.

Suppositories for rectal administration of the compounds of the presentinvention can be prepared by mixing the compound with a suitableexcipient such as cocoa butter, salicylates and polyethylene glycols.Formulations for vaginal administration can be in the form of a pessary,tampon, cream, gel, paste, foam, or spray formula containing, inaddition to the active ingredient, such suitable carriers as are knownin the art.

For topical administration the pharmaceutical composition can be in theform of creams, ointments, liniments, lotions, emulsions, suspensions,gels, solutions, pastes, powders, sprays, and drops suitable foradministration to the skin, eye, ear or nose. Topical administration mayalso involve transdermal administration via means such as transdermalpatches.

Aerosol formulations suitable for administering via inhalation also canbe made. For example, for treatment of disorders of the respiratorytract, the compounds according to the invention can be administered byinhalation in the form of a powder (e.g., micronized) or in the form ofatomized solutions or suspensions. The aerosol formulation can be placedinto a pressurized acceptable propellant.

The compounds can be administered as the sole active agent or incombination with other pharmaceutical agents such as other agents usedin the treatment of cognitive impairment and/or in the treatment ofpsychosis, e.g., other PDE4 inhibitors, calcium channel blockers,chloinergic drugs, adenosine receptor modulators, amphakines NMDA-Rmodulators, mGluR modulators, and cholinesterase inhibitors (e.g.,donepezil, rivastigimine, and glanthanamine). In such combinations, eachactive ingredient can be administered either in accordance with theirusual dosage range or a dose below its usual dosage range.

The present invention further includes methods of treatment that involveinhibition of PDE4 enzymes. Thus, the present invention includes methodsof selective inhibition of PDE4 enzymes in animals, e.g., mammals,especially humans, wherein such inhibition has a therapeutic effect,such as where such inhibition may relieve conditions involvingneurological syndromes, such as the loss of memory, especially long-termmemory. Such methods comprise administering to an animal in needthereof, especially a mammal, most especially a human, an inhibitoryamount of a compound, alone or as part of a formulation, as disclosedherein.

The condition of memory impairment is manifested by impairment of theability to learn new information and/or the inability to recallpreviously learned information. Memory impairment is a primary symptomof dementia and can also be a symptom associated with such diseases asAlzheimer's disease, schizophrenia, Parkinson's disease, Huntington'sdisease, Pick's disease, Creutzfeld-Jakob disease, HIV, cardiovasculardisease, and head trauma as well as age-related cognitive decline.

Dementias are diseases that include memory loss and additionalintellectual impairment separate from memory. The present inventionincludes methods for treating patients suffering from memory impairmentin all forms of dementia. Dementias are classified according to theircause and include: neurodegenerative dementias (e.g., Alzheimer's,Parkinson's disease, Huntington's disease, Pick's disease), vascular(e.g., infarcts, hemorrhage, cardiac disorders), mixed vascular andAlzheimer's, bacterial meningitis, Creutzfeld-Jacob Disease, multiplesclerosis, traumatic (e.g., subdural hematoma or traumatic braininjury), infectious (e.g., HIV), genetic (down syndrome), toxic (e.g.,heavy metals, alcohol, some medications), metabolic (e.g., vitamin B12or folate deficiency), CNS hypoxia, Cushing's disease, psychiatric(e.g., depression and schizophrenia), and hydrocephalus.

The present invention includes methods for dealing with memory lossseparate from dementia, including mild cognitive impairment (MCI) andage-related cognitive decline. The present invention includes methods oftreatment for memory impairment as a result of disease. In anotherapplication, the invention includes methods for dealing with memory lossresulting from the use of general anesthetics, chemotherapy, radiationtreatment, post-surgical trauma, and therapeutic intervention.

The compounds may be used to treat psychiatric conditions includingschizophrenia, bipolar or manic depression, major depression, and drugaddiction and morphine dependence. These compounds may enhancewakefulness. PDE4 inhibitors can be used to raise cAMP levels andprevent neurons from undergoing apoptosis. PDE4 inhibitors are alsoknown to be anti-inflammatory. The combination of anti-apoptotic andanti-inflammatory properties make these compounds useful to treatneurodegeneration resulting from any disease or injury, includingstroke, spinal cord injury, neurogenesis, Alzheimer's disease, multiplesclerosis, amylolaterosclerosis (ALS), and multiple systems atrophy(MSA).

Thus, in accordance with a preferred embodiment, the present inventionincludes methods of treating patients suffering from memory impairmentdue to, for example, Alzheimer's disease, schizophrenia, Parkinson'sdisease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease,depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility,multiinfarct dementia and other neurological conditions including acuteneuronal diseases, as well as HIV and cardiovascular diseases,comprising administering an effective amount of a compound according toFormula I or II or pharmaceutically acceptable salts thereof.

The compounds of the present invention can also be used in a method oftreating patients suffering from disease states characterized bydecreased NMDA function, such as schizophrenia. The compounds can alsobe used to treat psychosis characterized by elevated levels of PDE 4,for example, various forms of depression, such as manic depression,major depression, and depression associated with psychiatric andneurological disorders.

As mentioned, the compounds of the invention also exhibitanti-inflammatory activity. As a result, the inventive compounds areuseful in the treatment of a variety of allergic and inflammatorydiseases, particularly disease states characterized by decreased cyclicAMP levels and/or elevated phosphodiesterase 4 levels. Thus, inaccordance with a further embodiment of the invention, there is provideda method of treating allergic and inflammatory disease states,comprising administering an effective amount of a compound according toFormulas I or II or a pharmaceutically acceptable salt thereof. Suchdisease states include: asthma, chronic bronchitis, chronic obstructivepulmonary disease (COPD), atopic dermatitis, urticaria, allergicrhinitis, allergic conjunctivitis, vernal conjunctivitis, esoniophilicgranuloma, psoriasis, inflammatory arthritis, rheumatoid arthritis,septic shock, ulcerative colitis, Crohn's disease, reperfusion injury ofthe myocardium and brain, chronic glomerulonephritis, endotoxic shock,adult respiratory distress syndrome, cystic fibrosis, arterialrestenosis, artherosclerosis, keratosis, rheumatoid spondylitis,osteoartlritis, pyresis, diabetes mellitus, pneumoconiosis, chronicobstructive airways disease, chronic obstructive pulmonary disease,toxic and allergic contact eczema, atopic eczema, seborrheic eczema,lichen simplex, sunburn, pruritis in the anogenital area, alopeciaareata, hypertrophic scars, discoid lupus erythermatosus, systemic lupuserythematosus, follicular and wide-area pyodermias, endogenous andexogenous acne, acne rosacea, Beghet's disease, anaphylactoid purpuranephritis, inflammatory bowel disease, leukemia, multiple sclerosis,gastrointestinal diseases, autoimmune diseases and the like.

PDE4 inhibitors for treating asthma, chronic bronchitis, psoriasis,allergic rhinitis, and other inflammatory diseases, and for inhibitingtumor necrosis factor are known within the art. See, e.g., WO 98/58901,JP-11-18957, JP 10-072415, WO 93/25517, WO 94/14742, U.S. Pat. Nos.5,814,651, and 5,935,9778. These references also describe assays fordetermining PDE4 inhibition activity, and methods for synthesizing suchcompounds. The entire disclosures of these documents are herebyincorporated by reference.

PDE4 inhibitors may be used to prevent or ameliorate osteoporosis, as anantibiotic, for treatment of cardiovascular disease by mobilizingcholesterol from atherosclerotic lesions, to treat rheumatoid arthritis(RA), for long-term inhibition of mesenchymal-cell proliferation aftertransplantation, for treatment of urinary obstruction secondary tobenign prostatic hyperplasia, for suppression of chemotaxis andreduction of invasion of colon cancer cells, for treatment of B cellchronic lymphocytic leukemia (B-CLL), for inhibition of uterinecontractions, to attenuate pulmonary vascular ischemia-reperfusioninjury (IRI), for comeal hydration, for inhibition of IL-2R expressionand thereby abolishing HIV-1 DNA nuclear import into memory T cells, foraugmentation of glucose-induced insulin secretion, in both theprevention and treatment of colitis, and to inhibit mast celldegranulation.

The compounds of the present invention can be administered as the soleactive agent or in combination with other phaamaceutical agents such asother agents used in the treatment of cognitive impairment and/or in thetreatment of psychosis, e.g., other PDE4 inhibitors, calcium channelblockers, chloinergic drugs, adenosine receptor modulators, amphakinesNMDA-R modulators, mGluR modulators, and cholinesterase inhibitors(e.g., donepezil, rivastigimine, and glanthanamine). In suchcombinations, each active ingredient can be administered either inaccordance with their usual dosage range or a dose below their usualdosage range.

The dosages of the compounds of the present invention depend upon avariety of factors including the particular syndrome to be treated, theseverity of the symptoms, the route of administration, the frequency ofthe dosage interval, the particular compound utilized, the efficacy,toxicology profile, pharmacokinetic profile of the compound, and thepresence of any deleterious side-effects, among other considerations.

The compounds of the invention are typically administered at dosagelevels and in a mammal customary for PDE4 inhibitors such as those knowncompounds mentioned above. For example, the compounds can beadministered, in single or multiple doses, by oral administration at adosage level of, for example, 0.01-100 mg/kg/day, preferably 0.1-70mg/kg/day, especially 0.5-10 mg/kg/day. Unit dosage forms can contain,for example, 0.1-50 mg of active compound. For intravenousadministration, the compounds can be administered, in single or multipledosages, at a dosage level of, for example, 0.001-50 mg/kg/day,preferably 0.001-10 mg/kg/day, especially 0.01-1 mg/kg/day. Unit dosageforms can contain, for example, 0.1-10 mg of active compound.

In carrying out the procedures of the present invention it is of courseto be understood that reference to particular buffers, media, reagents,cells, culture conditions and the like are not intended to be limiting,but are to be read so as to include all related materials that one ofordinary skill in the art would recognize as being of interest or valuein the particular context in which that discussion is presented. Forexample, it is often possible to substitute one buffer system or culturemedium for another and still achieve similar, if not identical, results.Those of skill in the art will have sufficient knowledge of such systemsand methodologies so as to be able, without undue experimentation, tomake such substitutions as will optimally serve their purposes in usingthe methods and procedures disclosed herein.

The entire disclosures of all applications, patents and publications,cited above and below, and of U.S. Provisional Application No.60/396,726, filed Jul. 19, 2002, are hereby incorporated by reference.

EXAMPLES

The present invention will now be further described by way of thefollowing non-limiting examples. In applying the disclosure of theseexamples, it should be kept clearly in mind that other and differentembodiments of the methods disclosed according to the present inventionwill no doubt suggest themselves to those of skill in the relevant art.

In the foregoing and in the following examples, all temperatures are setforth uncorrected in degrees Celsius; and, unless otherwise indicated,all parts and percentages are by weight.

Example 1 6-Amino-1-cyclopentyl-3-ethyl-1H-indazole

To a mixture of 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid (258mg) and triethylamine (0.56 mL) in t-butanol (1 ml) was addeddiphenylphosphoryl azide (0.33 mL). The mixture was stirred at 100° C.for 4 h, then partitioned between water (25 mL) and ether (25 mL). Theether layer was collected, dried (MgSO₄), and passed through a plug ofsilica. The silica was washed with an additional 25 mL of ether and themixture was concentrated in vacuo. The residue was dissolved in THF (5mL) and 6N aq. HCL (1 mL) was added and the mixture was stirred for 18h. Ether (25 mL) and water (25 mnL) were added and the ether layer wascollected, dried (MgSO₄), and concentrated in vacuo. The residue waspurified by column chromatography on silica gel to yield 0.14 g of6-amino-1-cyclopentyl-3-ethyl-1H-indazole (59% yield). ¹H NMR (300 MHz)δ 7.45 (d, J=8.4 Hz, 1H), 6.52 (m,2H), 4.74 (p,J=7.8 Hz, 1H), 3.86(br,2H), 2.95 (q,J=7.7 Hz, 2H), 2.3-1.8 (m,6H), 1.8-1.6 (m,2H), 1.37(t,J=7.7 Hz, 3H).

Example 2 1-Cyclopentyl-3-ethyl-6-[N-(3-pyridylmethyl)]amino-1H-indazole

To a mixture of 3-pyridinecarboxaldehyde (106 mg, 1.0 mol) in methanol(5.0 mL) was added 6-amino-1-cyclopentyl-3-ethyl-1H-indazole (240 mg,1.05 mmol) and p-toluenesulfonic acid monohydrate (2.0 mg). The reactionmixture was stirred for 4 h. The flask was then cooled to 0° C. andsodium borohydride (0.09 g, 2.3 mmol) was added portion-wise over 4 h.The reaction fixture was allowed to warm to room temperature over 16 hwith stirring. TLC indicated the reaction was complete (1:3 hex:EA). Thesolvent was evaporated and diluted with water (10 mL) and extracted withethyl acetate (2×20 mL). The combined organic layers were washed withbrine (5 mL), dried over sodium sulfate, and concentrated to yield thedesired product. ¹H NMR (300 MHz) δ 8.64 (s, 1H), 8.51 (m,1H), 7.70 (m,1H), 7.42 (d, J=8.4 Hz, 1H), 7.25 (m, 1H), 6.50 (m,1H), 6.33 (s,1H),4.68 (p,J=7.8 Hz, 1H), 4.55 (br,1H), 4.40 (s,1H), 2.90 (q,J=7.7 Hz, 2H),2.1-1.8 (m,6H), 1.8-1.6 (m,2H), 1.34 (t,J=7.7 Hz, 3H).

The following compounds were prepared in a similar manner as describedabove in Example 2.

-   1-Cyclopentyl-6-(3-pyridylmethyl)aminoindazole,-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-(3-pyridylmethyl)]aminobenzofuran,    and-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-(4-pyridylmethyl)]aminobenzofuran.

Example 36-Amino-1-cyclopentyl-3-ethyl-6-[N-3-(1,1-dimethylethoxycarbonyl)phenyl]-N-(3-pyridylmethyl)amino-1H-indazole

To a 10 mL oven dried, argon flushed flask was added in the followingorder 0.06 g (0.61 mmol) of NaOtBu, 36 mg of Pd₂dba₃, 2.0 mL of toluene,0.014 mL of P(tBu)₃, and a 2.0 mL solution of 140 mg (0.436 mmol) of6-amino-1-cyclopentyl-3-ethyl-N-(3-pyridylmethyl)-1H-indazole intoluene. With stirring, 310 mg (1.5 mmol) of tert-butyl 3-iodobenzoatewas added dropwise and the mixture was stirred for 18 hours. Thereaction mixture was diluted with EtOAc and washed twice with H₂O andextracted with 3×15 mL of 3N HCl. The combined acid extracts were washedwith 15 mL of EtOAc and then carefully neutralized with 6N NaOH to pHgreater than 12. The basic solution was extracted with 2×15 mL of EtOAcand the combined organic fractions were subsequently washed with 15 mLof H₂O and brine, dried (MgSO₄), and concentrated. The residue waspurified by chromatography over silica gel (Biotage Flash 40M) elutingwith 25% EtOAc in hexanes. ¹H NMR (300 MHz) δ 8.65 (br, 1H), 8.51(br,1H), 8.26 (d, J=8.4, 1H), 7.75 (m, 1H), 7.7-7.5 (m, 3H), 7.27 (m,1H), 7.1-7.0 (m, 2H), 6.85 (d, J=8.4, 1H), 5.22 (s,1H), 4.76 (p,J=7.8Hz, 1H), 2.96 (q,J=7.7 Hz, 2H), 2.1-1.8 (m,6H), 1.8-1.6 (m,2H), 1.54(s,9H), 1.34 (t,J=7.7 Hz, 3H).

The following compounds were prepared in a similar manner as describedabove in Example 3.

-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-phenyl-N-(4-pyridylmethyl)]aminobenzofuran,-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-(4-cyanophenyl)-N-(3-pyridylmethyl)]aminobenzofuran,-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-(3-cyanophenyl)-N-(3-pyridylmethyl)]aminobenzofuran,-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-phenyl-N-(3-pyridylmethyl)]aminobenzofuran,-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-(3-cyanophenyl)-N-(4-pyridylmethyl)]aminobenzofuran,-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-(4-acetylphenyl)-N-(3-pyridylmethyl)]aminobenzofuran,-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-(4-carboxyphenyl)-N-(3-pyridylmethyl)]aminobenzofuran,-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-(4-(2H-tetrazol-5-yl)phenyl)-N-(3-pyridylmethyl]aminobenzofuran,-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-(4-carboxy-3-chlorophenyl)-N-(3-pyridylmethyl)]aminobenzofuran,-   7-Methoxy-2-(2-methyl-(1,3-dioxolane-2-yl))-4-[N-(3-carboxy-5-fluorophenyl)-N-(3-pyridylmethyl)]aminobenzofuran,-   1-Cyclopentyl-6-[N-phenyl-N-(3-pyridylmethyl)]aminoindazole, and-   1-Cyclopentyl-6-[N-(3-(1,1-dimethylethoxycarbonyl)phenyl)-N-(3-pyridylmethyl)]-1H-aminoindazole.

Example 46-Amino-1-Cyclopentyl-3-ethyl-6-[N-(3-carboxyphenyl)-N-(3-pyridylmethyl)]amino-1H-indazole

A solution consisting of 170 mg (0.344 mmol) of6-amino-1-cyclopentyl-3-ethyl-N-[3-(1,1-dimethylethoxycarbonyl)phenyl]-N-(3-pyridylmethyl)-1H-indazole,3.35 mL of dichloromethane and 0.84 mL of trifluoroacetic acid wasstirred at room temperature for 5 hours. The solution was washed with5.0 mL of H₂O. Then 5.0 mL of H₂O was added and the pH adjusted to 6 bythe addition of 10% aqueous NaOH. The combined aqueous layers wereextracted with 2×5 mL of dichloromethane. The combined dichloromethaneextracts were evaporated and the remaining material was purified byflash chromatography over SiO₂ using 10% MeOH in CH₂Cl₂ as eluant. ¹HNMR (300 MHz) δ 8.90 (br, 1H), 8.70 (br,1H), 8.25 (d, J=8.4, 1H),7.7-7.5 (m, 4H), 7.20 (m, 1H), 7.1-7.0 (m, 2H), 6.86 (d, J=8.4, 1H),5.20 (s,1H), 4.76 (p,J=7.8 Hz, 1H), 2.96 (q,J=7.7 Hz,2H), 2.05 (m,4H),1.88 (m,2H), 1.65 (m,2H), 1.36 (t,J=7.7 Hz, 3H).

The following compound was prepared in a similar manner as describedabove in Example 4.

-   1-Cyclopentyl-6-[N-(3-carboxyphenyl)-N-(3-pyridylmethyl)]aminoindazole.

Example 5 2-Acetyl-7-methoxy-4-nitrobenzofuran

To a solution of 2-acetyl-7-methoxybenzofuran (4.0 g) in aceticanhydride (50 mL) at 0° C. was added 70% nitric acid (1.5 mL) drop-wise.The mixture was warmed to room temperature and stirred for 3 h thenpoured into ice-cold saturated sodium carbonate (200 mL). Solid sodiumcarbonate was added carefully with stirring until basic (pH=8). Themixture was filtered and the solid collected by vacuum filtration. Thesolid was boiled in 100 mL (methanol) for 1 h, then cooled to 0° C. andfiltered to give 2-acetyl-7-methoxy-4-nitrobenzpfuran (2.1 g). ¹H NMR(300 MHz) δ 8.29 (d,J=8.9 Hz, 1H), 8.14 (s,1H), 7.00 (d,J=8.9 Hz, 1H),4.14 (s,3H), 2.68 (s, 3H).

Example 6 7-Methoxy-2-(2-methyl-(1,3-dioxotan-2-yl))-4-nitrobenzofuran

A mixture of 2-acetyl-7-methoxy-4-nitrobenzofuran (2.1 g), ethyleneglycol (2 mL), and p-toluensulfonic acid (25 mg) in toluene (50 mL) waswarmed to reflux with an attached Dean-Stark apparatus for 18 h. Themixture partitioned between sat. aq. NaHCO₃ (50 mL) and ether (50 mL).The ether layer was collected, washed with water (25 mL) and brine (25mL), dried (MgSO₄) and concentrated to give pure7-methozy-2-(2-methyl-(1,3-dioxolan-2-yl))-4-nitrobenzofuran (2.1 g). ¹HNMR (300 MHz) δ 8.22 (d,J=9.0 Hz, 1H), 7.44 (s,1H), 6.84 (d,J=9.0 Hz,1H), 4.11 (s,3H), 4.11 (m,4H), 1.86 (s,3H).

Example 7 4-Amino-7-methoxy-2-(2-methyl-(1,3-dioxolan-2-yl))-benzofuran

To a suspension of 10% Pd on activated carbon (200 mg) in ethanol (100mL), under N₂ protection, was added7-methoxy-2-(2-methyl-(1,3-dioxolan-2-yl))-4-nitrobenzofuran (6.50 g, 23mmol). The reaction mixture was degassed under vacuum three times. Thereaction mixture was stirred vigorously while hydrogen gas was allowedto flow over the reaction mixture. After 4 h the reaction was completeby TLC (5:1 hex:EA). The reaction mixture was filtered through a pad ofcelite and the celite was rinsed with additional ethanol. The solventwas removed in-vacuo to obtain 5.1 g (88% yield) of the title compoundas a yellow oil.

Example 82-Acetyl-7-methoxy-4-(N-(3-carboxyphenyl)-N-(3-pyridylmethyl)aminobenzofuran

7-Methoxy-2-(2-methyl-1,3-dioxolan-2-yl)-4-(N-3-carboxyphenyl)-N-(3-pyridylmethyl)aminobenzofuran,t-butyl ester (120 mg) was taken up in CH₂Cl₂ (10 mL) andtrifluoroacetic acid (2 mL) was added and the mixture was stirred for 4h. The mixture was concentrated in vacuo and the residue was purified bycolumn chromatography eluting with a linear gradient from 0%-10% MeOH inEtOAc over 15 min to yield 65 mg of2-acetyl-7-methoxy-4-(N-(3-carboxyphenyl)-N-)3-pyridylmethyl)aminobenzofuran.¹H NMR (300 MHz) □ 11.60 (br,1H,) 8.71 (br,1H), 8.56 (br,1H), 7.80(d,J=7.5 Hz, 1H), 7.60-7>50 (m,2H), 7.35 (m,1H), 7.20 (t,J=7.9 Hz, 1H),7.10-7.00 (m,2H), 6.95-6.80 (m,2H), 5.09 (s,2H), 4.01 (s,3H), 2.54(s,3H).

The following compounds were prepared in a similar manner as describedabove in Example 8.

-   2-Acetyl-7-methoxy-4-[N-phenyl-N-(4-pyridylmethyl)]aminobenzofuran,-   2-Acetyl-7-methoxy-4-[N-(4-cyanophenyl)-N-(3-pyridylmethyl)]aminobenzofuran,-   2-Acetyl-7-methoxy-4-[N-(3-cyanophenyl)-N-(3-pyridylmethyl)]aminobenzofuran,-   2-Acetyl-7-methoxy-4-[N-phenyl-N-(3-pyridylmethyl)]aminobenzofuran,-   2-Acetyl-7-methoxy-4-[N-(3-cyanophenyl)-N-(4-pyridylmethyl)]aminobenzofuran,-   2-Acetyl-7-methoxy-4-[N-(4-acetylphenyl)-N-(3-pyridylmethyl)]aminobenzofuran,-   2-Acetyl-7-methoxy-4-[N-(4-carboxyphenyl)-N-(3-pyridylmethyl)]aminobenzofuran,-   2-Acetyl-7-methoxy-4-[N-(4-(2H-tetrazol-5-yl)phenyl)-N-(3-pyridylmethyl]aminobenzofuran,-   2-Acetyl-7-methoxy-4-[N-(4-carboxy-3-chlorophenyl)-N-(3-pyridylmethyl)]aminobenzofuran,    and-   2-Acetyl-7-methoxy-4-[N-(3-carboxy-5-fluorophenyl)-N-(3-pylidylmethyl)]aminobenzofuran.

Example 92-Acetyl-7-methoxy-N-(4-phenylsulfonylaminocarbonylphenyl)-N-(3-pyridylmethyl)-4-aminobenzofuran

To a solution of2-acetyl-7-methoxy-N-(4-carboxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzofuran(416 mg, 1.0 mmol), benzenesulfonamide (200 mg, 1.2 mmol), and DMAP (150mg, 1.2 mmol) in dichloromethane (5 mL) at room temperature was addedEDCI (230 mg, 1.2 mmol) in one portion and the mixture was stirred atroom temperature for 16 h. The mixture was partitioned between water (25mL) and EtOAc (25 mL) and the pH was adjusted to 5-6 with 1.0 N HCl. TheEtOAc was separated, washed with brine (25 mL), dried (MgSO₄) andconcentrated in vacuo. The residue was purified by column chromatographyeluting with a linear gradient from 5% to 10% MeOH in EtOAc to give2-Acetyl-7-methoxy-N-(4-phenylsulfonylaminocarbonylphenyl)-N-(3-pyridylmethyl)-4-aminobenzofuran(415 mg). ¹H NMR (300 MHz) δ 8.53 (br,1H), 8.46 (br,1H), 8.06 (d,J=7.3Hz,2H), 7.8-7.3 (m,6H), 7.21 (m,1H), 7.1-7.0 (m,2H), 6.91 (d,J=8.5Hz,1H), 6.56 (d,J=7.3 Hz,2H), 4.99 (s,2H), 4.02 (s,3H), 2.54 (s,3H).

Example 10 In Vitro Measurement of Type 4 Phosphodiesterase InhibitionActivity

Human PDE4 was obtained from baculovirus-infected Sf9 cells thatexpressed the recombinant enzyme. The cDNA encoding hPDE-4D6 wassubcloned into a baculovirus vector. Insect cells (Sf9) were infectedwith the baculovirus and cells were cultured until protein wasexpressed. The baculovirus-infected cells were lysed and the lysate wasused as source of HPDE-4D6 enzyme. The enzyme was partially purifiedusing a DEAE ion exchange chromatography. This procedure can be repeatedusing cDNA encoding other PDE-4 enzymes.

Assay:

Type 4 plhosphodiesterases convert cyclic adenosine monophosphate (cAMP)to 5′-adenosine monophlosphate (5′-AMP). Nucleotidase converts 5′-AMP toadenosine. Therefore the combined activity of PDE4 and nucleotidaseconverts cAMP to adenosine. Adenosine is readily separated from cAMP byneutral alumina columns. Phosphodiesterase inhibitors block theconversion of cAMP to adenosine in this assay; consequently, PDE4inhibitors cause a decrease in adenosine.

Cell lysates (40 ul) expressing hPDE-4D6 were combined with 50 ul ofassay mix and 10 ul of inhibitors and incubated for 12 min at roomtemperature. Final concentrations of assay components were: 0.4 ugenzyme, 10 mM Tris-HCl (pH 7.5), 10 mM MgCl₂, 3 uM cAMP, 0.002 U5′-nucleotidase, and 3×10⁴ cpm of [3H]cAMP. The reaction was stopped byadding 100 μl of boiling 5 mN HCl. An aliquot of 75 μl of reactionmixture was transferred from each well to alumina columns (Multiplate;Millipore). Labeled adenosine was eluted into an OptiPlate by spinningat 2000 rpm for 2 min; 150 μl per well of scintillation fluid was addedto the OptiPlate. The plate was sealed, shalken for about 30 min, andcpm of [³H]adenosine was determined using a Wallac Triflux®.

All test compounds are dissolved in 100% DMSO and diluted into the assaysuch that the final concentration of DMSO is 0.1%. DMSO does not affectenzyme activity at this concentration.

A decrease in adenosine concentration is indicative of inhibition of PDEactivity. pIC₅₀ values were determined by screening 6 to 12concentrations of compound ranging from 0.1 nM to 10,000 nM and thenplotting drug concentration versus ³H-adenosine concentration. Nonlinearregression software (Assay Explorer®) was used to estimate pIC₅₀ values.

Example 11 (Method A) Passive Avoidance in Rats, an in vivo Test forLearning and Memory

The test was performed as previously described (Zhang, H.-T., Crissman,A. M., Dorairaj, N. R., Chandler, L. J., and O'Donnell, J. M.,Neuropsychopharmacology, 2000, 23, 198-204. ). The apparatus (ModelE10-16SC, Coulboum Instruments, Allentown, Pa.) consisted of atwo-compartment chamber with an illuminated compartment connected to adarkened compartment by a guillotine door. The floor of the darkenedcompartment consisted of stainless steel rods through which an electricfoot-shock could be delivered from a constant current source. Allexperimental groups were first habituated to the apparatus the daybefore the start of the experiment. During the training, the rat (MaleSpraque-Dawley (Harlan) weighing 250 to 350 g) was placed in theilluminated compartment facing away from the closed guillotine door for1 minute before the door was raised. The latency for entering thedarkened compartment was recorded. After the rat entered the darkenedcompartment, the door was closed and a 0.5 mA electric shock wasadministered for 3 seconds. Twenty-four hours later, the rat wasadministered 0.1 mg/kg MK-801 or saline, 30 minutes prior to theinjection of saline or test compound (dosed from 0.1 to 2.5 mg/kg,i.p.), which was 30 minutes before the retention test started. The ratwas again placed in the illuminated compartment with the guillotine dooropen. The latency for entering the darkened compartment was recorded forup to 180 seconds, at which time the trial was terminated.

All data were analyzed by analyses of variance (ANOVA); individualcomparisons were made using Kewman-Keuls tests. Naive rats required lessthan 30 seconds, on average, to cross from the illuminated compartmentto the darkened compartment. However, 24 hours after the electric shockexposure, most rats pretreated with vehicle did not re-enter thedarkened compartment; the average latency was increased up to 175seconds (p<0.001). Pretreatment with MIK-801 (0.1 mg/kg) markedlyreduced this latency when compared to the vehicle (p<0.001). Thisamnesic effect of MK-801 is reversed in a statistically significantmanner by actual test compounds in a dose-dependent fashion.

Example 11 (Method B) Radial Arm Maze Task in Rats, an In Vivo Test forLearning and Memory

The test was performed as previously described (Zhang, H.-T., Crissman,A. M., Dorairaj, N. R., Chandler, L. J., and O'Donnell, J. M.,Neuropsychopharmacolog, 2000, 23, 198-204. ). Five days after initialhousing, rats (male Spraque-Dawley (Harlan) weighing 250 to 350 g) wereplaced in the eight-arm radial maze (each arm was 60×10×12 cm high; themaze was elevated 70 cm above the floor) for acclimation for two days.Rats were then placed individually in the center of the maze for 5minutes with food pellets placed close to the food wells, and then, thenext day, in the wells at the end of the arms; 2 sessions a day wereconducted. Next, four randomly selected arms were then baited with onepellet of food each. The rat was restricted to the center platform (26cm in diameter) for 15 seconds and then allowed to move freelythroughout the maze until it collected all pellets of food or 10 minutespassed, whichever came first. Four parameters were recorded: 1) workingmemory errors, i.e., entries into baited anrns that had already beenvisited during the same trial; 2) reference memory errors, i.e., entriesinto unbaited arms; 3) total arm entries; and 4) the test duration(seconds), i.e., the time spent in the collection of all the pellets inthe maze. If the working memory error was zero and the average referencememory enror was less than one in five successive trials, the rats beganthe drug tests. MK-801 or saline was injected 15 minutes prior tovehicle or test agent, which was given 45 minutes before the test.Experiments were performed in a lighted room, which contained severalextra-maze visual cues.

All data were analyzed by analyses of variance (ANOVA); individualcomparisons were made using Kewman-Keuls tests. Compared to control,MK-801 (0.1 mg/kg, i.p.) increased the frequencies of both working andreference memory errors (p<0.01). This amnesic effect of MK-801 onworking memory is reversed in a statistically significant manner by theadministration of actual test compounds in a dose-dependent fashion.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

While the invention has been illustrated with respect to the productionand of particular compounds, it is apparent that variations andmodifications of the invention can be made without departing from thespirit or scope of the invention.

1. A compound of the formula I:

wherein R¹ is H, alkyl having 1 to 8 carbon atoms, which is branched orunbranched and which is unsubstituted or substituted one or more timesby halogen, cycloalkyl having 3 to 10 carbon atoms, which isunsubstituted or substituted one or more times by halogen, hydroxy, oxo,cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbonatoms, or combinations thereof, or a heterocyclic group, which issaturated, partially saturated or unsaturated, having 5 to 10 ring atomsin which at least 1 ring atom is a N, O or S atom, which isunsubstituted or substituted one or more times by halogen, alkyl,hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy,trifluoromethyl, amino, aminomethyl, alkylamino, aminoalkoxy,dialkylamino, hydroxyalkyl, —C(O)—NHOH, tetrazole-5-yl, hydroxyalkoxy,carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl,alkylsulfonyl, phenoxy, or combinations thereof; R² is H, or alkylhaving 1 to 4 carbon atoms, which is branched or unbranched and which isunsubstituted or substituted one or more times by halogen, cyano, and/orC₁₋₄-alkoxy, and where one or more —CH₂CH₂— groups are optionallyreplaced in each case by —CH═CH— or —C≡C—; R³ is a partially unsaturatedcarbocycle-alkyl group wherein the carbocyclic portion has 5 to 14carbon atoms and the alkyl portion which is branched or unbranched has 1to 5 carbon atoms, and which is unsubstituted or substituted in thecarbocyclic portion one or more times by halogen, alkyl, alkoxy, nitro,cyano, oxo, or combinations thereof, and the alkyl portion is optionallysubstituted by halogen, C₁₋₄-alkoxy, cyano or combinations thereof,arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to14 carbon atoms and the alkyl portion, which is branched or unbranched,has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted orsubstituted, in the aryl portion, one or more times by halogen,trifluoromethyl, CF₃O, nitro, amino, alkyl, alkoxy, alkylamino,dialkylamino and/or substituted in the alkyl portion by halogen, cyano,or methyl, or heterocyclic-alkyl group, wherein the heterocyclic portionmay be partially or fully saturated and has 5 to 10 ring atoms in whichat least 1 ring atom is a N, O or S atom, the alkyl portion, which isbranched or unbranched, has 1 to 5 carbon atoms, the heterocyclic-alkylgroup is unsubstituted or substituted one or more times in theheterocyclic portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl,CF₃O, nitro, amino, alkylamino, dialkylamino, or combinations thereofand/or substituted in the alkyl portion by halogen, cyano, or methyl orcombinations thereof; R⁴ is aryl having 6 to 14 carbon atoms and whichis unsubstituted or substituted one or more times by halogen, alkyl,alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy,ethylenedioxy, trifluoromethyl, OCF₃, amino, alkylamino, aminoalkoxy,dialkylamino, hydroxyalkyl, —C(O)—NHOH, tetrazole-5-yl,2(-heterocycle)tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl,cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy,trialkylsilyloxy, R⁵—L—, or combinations thereof, or heteroaryl selectedfrom furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl,oxathiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrazinyl, oxazinyl,isoxazinyl, oxathiazinyl, oxadiazinyl, benzofuranyl, isobenzofuranyl,thionaphthenyl, isothionaphthenyl, indolyl, isoindolyl, indazolyl,benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzisothiazolyl, purinyl,benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl,naphthyridinyl, and benzoxazinyl, which in each case is unsubstituted orsubstituted one or more times by halogen, alkyl, hydroxy, alkoxy,alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl,amino, aminomethyl, alkylamino, aminoalkoxy, dialkylamino, hydroxyalkyl,—C(O)—NHOH, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl,cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy,trialkylsilyloxy, R⁵—L—, or combinations thereof; R⁵ is H, alkyl having1 to 8 carbon atoms, which is unsubstituted or substituted one or moretimes with halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, oxo, or combinationsthereof, alkylamino or dialkylamino wherein each alkyl portion hasindependently 1 to 8 carbon atoms, a partially unsaturatedcarbocycle-alkyl group wherein the carbocyclic portion has 5 to 14carbon atoms and the alkyl portion has 1 to 5 carbon atoms, which isunsubstituted or substituted one or more times by halogen, alkyl,alkoxy, nitro, cyano, oxo, or combinations thereof, cycloalkyl having 3to 10 carbon atoms, which is unsubstituted or substituted one or moretimes by halogen, hydroxy, oxo, cyano, alkoxy, alkyl having 1 to 4carbon atoms, or combinations thereof, cycloalkylalkyl having 4 to 16carbon atoms, which is unsubstituted or substituted in the cycloalkylportion and/or the alkyl portion one or more times by halogen, oxo,cyano, hydroxy, alkyl, alkoxy or combinations thereof, aryl having 6 to14 carbon atoms which is unsubstituted or substituted one or more timesby halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy,ethylenedioxy, trifluoromethyl, amino, aminomethyl, alkylamino,aminoalkoxy, dialkylamino, hydroxyalkyl, —C(O)—NHOH, tetrazole-5-yl,hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio,alkylsulfinyl, alkylsulfonyl, or combinations thereof arylalkyl having 7to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atomsand the alkyl portion, which is branched or unbranched, has 1 to 5carbon atoms, arylalkyl radical is unsubstituted or substituted, in thearyl portion, one or more times by halogen, trifluoromethyl, CF₃O,nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino, orcombinations thereof, and/or substituted in the alkyl portion byhalogen, cyano, methyl, or combinations thereof, a heterocyclic group,which is saturated, partially saturated or unsaturated, having 5 to 10ring atoms in which at least 1 ring atom is a N, O or S atom, which isunsubstituted or substituted one or more times by halogen, alkyl,hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy,trifluoromethyl, amino, aminomethyl, alkylamino, aminoalkoxy,dialkylamino, hydroxyalkyl, —C(O)—NHOH, tetrazole-5-yl, hydroxyalkoxy,carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl,alkylsulfonyl, phenoxy, or combinations thereof, or a heterocycle-alkylgroup, wherein the heterocyclic portion is saturated, partiallysaturated or unsaturated, and has 5 to 10 ring atoms in which at least 1ring atom is a N, O or S atom, and the alkyl portion which is branchedor unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl groupis unsubstituted or substituted one or more times in the heterocyclicportion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF₃O, nitro,oxo, amino, alkylamino, dialkylamino, or combinations thereof and/orsubstituted in the alkyl portion by halogen, cyano, or methyl orcombinations thereof; L is a single bond or a divalent aliphatic radicalhaving up to 8 carbon atoms wherein one or more —CH₂— groups are eachoptionally replaced by —O—, —S—, —SO₂—, —SO—, —NR⁶—, —SO₂NH—, —NHSO₂—,—CO—, —NR⁶CO—, —CONR⁶—, —NHCONH—, —OCONH—, —NHCOO—, —SCONH—, —SCSNH—, or—NHCSNH—; and R⁶ is H, or alkyl having 1 to 8 carbon atoms, which isbranched or unbranched and which is unsubstituted or substituted one ormore times with halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, oxo, or combinationsthereof; or a pharmaceutically acceptable salt thereof; wherein anoptically active compound can be in the form of one of its separateenantiomers or mixtures thereof, including racemic mixtures.
 2. Acompound of claim 1, which is of the subformula V:

wherein R¹ is H, alkyl having 1 to 8 carbon atoms, which is branched orunbranched and which is unsubstituted or substituted one or more timesby halogen, cycloalkyl having 3 to 10 carbon atoms, which isunsubstituted or substituted one or more times by halogen, hydroxy, oxo,cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbonatoms, or combinations thereof, or a heterocyclic group, which issaturated, partially saturated or unsaturated, having 5 to 10 ring atomsin which at least 1 ring atom is a N, O or S atom, which isunsubstituted or substituted one or more times by halogen, alkyl,hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy,trifluoromethyl, amino, aminomethyl, alkylamino, aminoalkoxy,dialkylamino, hydroxyalkyl, —C(O)—NHOH, tetrazole-5-yl, hydroxyalkoxy,carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl,alkylsulfonyl, phenoxy, or combinations thereof; R² is H, or alkylhaving 1 to 4 carbon atoms, which is branched or unbranched and which isunsubstituted or substituted one or more times by halogen, cyano, and/orC₁₋₄-alkoxy, and where one or more —CH₂CH₂— groups are optionallyreplaced in each case by —CH═CH—or —C≡C—; R⁴ is aryl having 6 to 14carbon atoms and which is unsubstituted or substituted one or more timesby halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy,nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF₃, amino,alkylamino, aminoalkoxy, dialkylamino, hydroxyalkyl, —C(O)—NHOH,tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl, hydroxyalkoxy, carboxy,alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl,phenoxy, trialkylsilyloxy, R⁵—L—, or combinations thereof, or heteroarylselected from furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxatriazolyl,dioxazolyl, oxathiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrazinyl,oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, benzofuranyl,isobenzofuranyl, thionaphthenyl, isothionaphthenyl, indolyl, isoindolyl,indazolyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl,benzisothiazolyl, purinyl, benzopyranyl, quinolinyl, isoquinolinyl,cinnolinyl, quinazolinyl, naphthyridinyl, and benzoxazinyl, which ineach case is unsubstituted or substituted one or more times by halogen,alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy,ethylenedioxy, trifluoromethyl, amino, aminomethyl, alkylamino,aminoalkoxy, dialkylamino, hydroxyalkyl, —C(O)—NHOH, tetrazole-5-yl,hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio,alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy, R⁵—L—, orcombinations thereof; and one of B, D and E is N and the other two areC; or a pharmaceutically acceptable salt thereof; wherein an opticallyactive compound can be in the form of one of its separate enantiomers ormixtures thereof, including racemic mixtures.
 3. A compound of claim 2,wherein D is N and B and E are C.
 4. A compound of claim 2, wherein R⁴is phenyl which is unsubstituted or substituted one or more times byhalogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro,methylenedioxy, ethylenedioxy, trifluoromethyl, OCF₃, amino, alkylamino,aminoalkoxy, dialkylamino, hydroxyalkyl, —C(O)—NHOH, tetrazole-5-yl,2(-heterocycle)tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl,cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy,trialkylsilyloxy, R⁵—L—, or combinations thereof.
 5. A compound of claim1, which is:1-Cyclopentyl-6-[N-(3-(1,1-dimethylethoxycarbonyl)phenyl)-N-(3-pyridylmethyl)]-1H-aminoindazoleor a pharmaceutically acceptable salt thereof,1-Cyclopentyl-6-(N-phenyl-N-(3-pyridylmethyl))aminoindazole or apharmaceutically acceptable salt thereof,1-Cyclopentyl-6-(N-(3-carboxyphenyl)-N-(3-pyridylmethyl)) aminoindazoleor a pharmaceutically acceptable salt thereof, or6-Amino-1-cyclopentyl-3-ethyl-6-[N-3-(1,1-dimethylethoxycarbonyl)phenyl]-N-(3-pyridylmethyl)amino-1H-indazoleor a pharmaceutically acceptable salt thereof, or1-Cyclopentyl-3-ethyl-6-[N-(3-carboxyphenyl)-N-(3-pyridylmethyl)]amino-1H-indazoleor a pharmaceutically acceptable salt thereof, wherein optically activecompounds can be in the form of their separate enantiomers or mixturesthereof, including racemic mixtures.
 6. A compound of claim 1, wherein:each aryl group is, independently, a phenyl, naphthyl or biphenyl groupoptionally substituted one or more times by halogen, alkyl, hydroxy,alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino,dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl,alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, orcombinations thereof; each heteroaryl group is, independently, a furyl,thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,oxatriazolyl, dioxazolyl, oxathiazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazinyl, isoxazinyl,oxathiazinyl, oxadiazinyl, benzofuranyl, isobenzofuranyl,thionaphthenyl, isothionaphthenyl, indolyl, isoindolyl,indazolyl,benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzisothiazolyl,purinyl, benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl,quinazolinyl, naphthyridinyl, or benzoxazinyl group optionallysubstituted in one or more places by halogen, aryl, alkyl, alkoxy,carboxy, cyano, trifluoromethyl, nitro, amino, alkylamino, dialkylamino,or combinations thereof; and each heterocycle group is, independently, aheteroaryl group as stated above or a tetrahydrofuranyl, piperidinyl, orpyrrolidinyl group optionally substituted as stated above.
 7. A compoundof claim 1, wherein: R¹ is an alkyl group having 2 to 4 carbon atomswhich is optionally substituted by fluorine or chlorine or iscyclopentyl or cyclohexyl; R² is H or alkyl having 1 to 4 carbon atoms;R³ is substituted or unsubstituted benzyl, phenethyl, or phenpropyl; orsubstituted or unsubstituted pyridylmethyl, furanylmethyl,thienylmethyl, pyrrolylmethyl, pyrimidinylmethyl, thiazolylmethyl,isoquinolinylmethyl or quinolinylmethyl; and R⁴ is phenyl, naphthyl,biphenyl, furanyl, pyrazinyl, pyridyl, quinolinyl, or isoquinolinyl,which in each case is unsubstituted or is substituted one or more timesby OH, F, Cl, CF₃, alkyl, alkoxy, CN, vinyl, CH₂OH, CONHOH,methylenedioxy or COOH, or R⁴ is phenyl, naphthyl, or biphenyl which ineach case is optionally substituted by R⁵—, R⁵—O—, R⁵—CO—, R⁵—NH—CO—,R⁵-SO₂—NH—, R⁵—SO₂—NH-alkylene-O—, NH₂-alkyl-NH—CO—, R⁵-alkylene-NH—CO—,alkyl-CO—NH-alkyl-, methyl, ethyl, Cl, F, CN, OCH₃, CF₃, amino, nitro,HOCH₂ COOH, or combinations thereof.
 8. A compound of claim 1, wherein:R³ is arylalkyl or heteroarylalkyl, in each case substituted orunsubstituted; and R⁴ is aryl or heteroaryl, in each case substituted orunsubstituted.
 9. A compound of claim 1, wherein: R¹ is cycloalkyl; andR² is H or C₂H₅.
 10. A compound of claim 1, wherein: R¹ is cycloalkyl;R² is H or C₂H₅; R³ is arylalkyl or heteroarylalkyl, in each casesubstituted or unsubstituted; and R⁴ is aryl or heteroaryl, in each casesubstituted or unsubstituted.
 11. A compound of claim 1, wherein: R¹ iscyclopentyl; R² is H or C₂H₅; R³ is arylalkyl or heteroarylalkyl, ineach case substituted or unsubstituted; and R⁴ is aryl or heteroaryl, ineach case substituted or unsubstituted.
 12. A compound of claim 1,wherein: R¹ is cyclopentyl; R² is H or C₂H₅; R³ is pyridyl which issubstituted or unsubstituted; and R⁴ is aryl or heteroaryl, in each casesubstituted or unsubstituted.
 13. A compound of claim 1, wherein: R¹ iscyclopentyl; R² is H or C₂H₅; R³ is pyridyl which is substituted orunsubstituted; and R⁴ is phenyl which is substituted or unsubstituted.14. A compound of claim 1, wherein: R³ is pyridyl which is substitutedor unsubstituted; and R⁴ is aryl or heteroaryl, in each case substitutedor unsubstituted.
 15. A compound of claim 1, wherein: R³ is pyridylwhich is substituted or unsubstituted; and R⁴ is phenyl which issubstituted or unsubstituted.
 16. A pharmaceutical compositioncontaining a compound of claim 1 and a pharmaceutically acceptablecarrier.
 17. A composition of claim 16, wherein the compound of isprovided in a unit dosage of 0.1-50 mg.
 18. A compound according toclaim 1, wherein R⁴is phenyl, naphthyl or biphenyl, which isunsubstituted or substituted one or more times by halogen, alkyl,hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino,alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano,acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy,or combinations thereof, and acyl is an alkanoyl radical having 1 to 13carbon atoms in which the alkyl portion is unsubstituted or substitutedby halogen, alkyl, aryl, alkoxy, or combinations thereof, or acyl is anaroyl radical having 7 to 15 carbon atoms in which the aryl portion isunsubstituted or substituted by halogen, alkyl, alkoxy or combinationsthereof.
 19. A compound according to claim 1, wherein R³ is benzyl,1-phenethyl, 2-phenethyl, phenpropyl, phenbutyl, phenpentyl, ornapthylmethyl.
 20. A compound according to claim 1, wherein R⁴ is furyl,thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,isoxazolyl, oxazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl,oxathiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrazinyl, oxazinyl,isoxazinyl, oxathiazinyl, oxadiazinyl, benzofuranyl, isobenzofuranyl,thionaphthenyl, isothionaphthenyl, indolyl, isoindolyl, indazolyl,benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzisothiazolyl, purinyl,benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl,naphthyridinyl, or benzoxazinyl, which in each case is unsubstituted orsubstituted in one or more places by halogen, aryl, alkyl, alkoxy,carboxy, cyano, trifluoromethyl, nitro, amino, alkylamino, dialkylamino,or combinations thereof.
 21. A compound according to claim 1, wherein R⁴is 2-thienyl, 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7- or8-quinolinyl, or 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, which ineach case is unsubstituted or substituted in one or more places byhalogen, aryl, alkyl, alkoxy, carboxy, cyano, trifluoromethyl, nitro,amino, alkylamino, dialkylamino, or combinations thereof.
 22. A compoundaccording to claim 1, wherein R³ is benzyl, benzyl substituted by F, Cl,CH₃, C₂H₅, OCH₃, CN, or combinations thereof, phenethyl, phenethylsubstituted by F, Cl, CH₃, C₂H₅, OCH₃, CN, or combinations thereof,phenpropyl, phenpropyl substituted by F, Cl, CH₃, C₂H₅, OCH₃ CN, orcombinations thereof, pyridylmethyl, pyridylmethyl substituted by are F,Cl, CH₃, C₂H5, OCH₃, CN, or combinations thereof, furanylmethyl,furanylmethyl substituted by are F, Cl, CH₃, C₂H₅, OCH₃ CN, orcombinations thereof, thienylmethyl, thienylmethyl substituted by are F,Cl, CH₃, C₂H₅, OCH₃, CN, or combinations thereof, pyrrolylmethyl,pyrrolylmethyl substituted by are F, Cl, CH₃, C₂H₅, OCH₃ CN, orcombinations thereof, pyrimidinylmethyl, pyrimidinylmethyl substitutedby are F, Cl, CH₃, C₂H₅, OCH₃ CN, or combinations thereof,thiazolylmethyl, thiazolylmethyl substituted by are F, Cl, CH₃, C₂H₅,OCH₃, CN, or combinations thereof, isoquinolinylmethyl,isoquinolinylmethyl substituted by are F, Cl, CH₃, C₂H₅, OCH₃, CN, orcombinations thereof, quinolinylmethyl, or quinolinylmethyl substitutedby are F, Cl, CH₃, C₂H₅, OCH₃, CN, or combinations thereof.
 23. Acompound according to claim 1, wherein R⁴ is phenyl, naphthyl, biphenyl,furanyl, pyrazinyl, pyridyl, quinolinyl, or isoquinolinyl, which in eachcase is unsubstituted or is substituted one or more times by OH, F, Cl,CF₃, methyl, ethyl, methoxy, ethoxy, CN, vinyl, CH₂OH, CONHOH,methylenedioxy, COOH, or combinations thereof.
 24. A compound accordingto claim 1, wherein R⁴ is phenyl which is unsubstituted or issubstituted one or more times by OH, F, Cl, CF₃, methyl, ethyl, methoxy,ethoxy, CN, vinyl, CH₂OH, CONHOH, methylenedioxy, COOH, or combinationsthereof.
 25. A compound according to claim 1, wherein R³ ispyridylmethyl.
 26. A compound according to claim 24, wherein R³ ispyridylmethyl.
 27. A compound according to formula I:

wherein R¹ is H, alkyl having 1 to 8 carbon atoms, which is branched orunbranched and which is unsubstituted or substituted one or more timesby halogen, cycloalkyl having 3 to 10 carbon atoms, which isunsubstituted or substituted one or more times by halogen, hydroxy, oxo,cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbonatoms, or combinations thereof, or a heterocyclic group, which issaturated, partially saturated or unsaturated, having 5 to 10 ring atomsin which at least 1 ring atom is a N, O or S atom, which isunsubstituted or substituted one or more times by halogen, alkyl,hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy,trifluoromethyl, amino, aminomethyl, alkylamino, aminoalkoxy,dialkylamino, hydroxyalkyl, —C(O)—NHOH, tetrazole-5 -yl, hydroxyalkoxy,carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl,alkylsulfonyl, phenoxy, or combinations thereof, R² is H, or alkylhaving 1 to 4 carbon atoms, which is branched or unbranched and which isunsubstituted or substituted one or more times by halogen, cyano, and/orC₁₋₄-alkoxy, and where one or more —CH₂CH₂— groups are optionallyreplaced in each case by —CH═CH— or —C≡C—, R³ is alkyl having 1 to 8carbon atoms, which is branched or unbranched, and which is substitutedone or more times with halogen, cyano, C₁₋₄-alkoxy, or combinationsthereof, a partially unsaturated carbocycle-alkyl group wherein thecarbocyclic portion has 5 to 14 carbon atoms and the alkyl portion whichis branched or unbranched has 1 to 5 carbon atoms, and which isunsubstituted or substituted in the carbocyclic portion one or moretimes by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinationsthereof, and the alkyl portion is optionally substituted by halogen,C₁-₄-alkoxy, cyano or combinations thereof, arylalkyl having 7 to 19carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and thealkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms,arylalkyl radical is unsubstituted or substituted, in the aryl portion,one or more times by halogen, trifluoromethyl, CF₃O, nitro, amino,alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the alkylportion by halogen, cyano, or methyl, or heterocyclic-alkyl group,wherein the heterocyclic portion may be aromatic, or partially or fullysaturated and has 5 to 10 ring atoms in which at least 1 ring atom is aN, O or S atom, the alkyl portion, which is branched or unbranched, has1 to 5 carbon atoms, the heterocyclic-alkyl group is unsubstituted orsubstituted one or more times in the heterocyclic portion by halogen,alkyl, alkoxy, cyano, trifluoromethyl, CF₃O, nitro, amino, alkylamino,dialkylamino, or combinations thereof and/or substituted in the alkylportion by halogen, cyano, or methyl or combinations thereof; R⁴ is arylhaving 6 to 14 carbon atoms and which is unsubstituted or substitutedone or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl,OCF₃, amino, alkylamino, aminoalkoxy, dialkylamino, hydroxyalkyl,—C(O)—NHOH, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl,hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio,alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy, R⁵—L—, orcombinations thereof, or heteroaryl selected from furyl, thienyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl,oxazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrazinyl, oxazinyl, isoxazinyl,oxathiazinyl, oxadiazinyl, benzofuranyl, isobenzofuranyl,thionaplithenyl, isothionaplithenyl, indolyl, isoindolyl, indazolyl,benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzisothiazolyl, purinyl,benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl,naplithyridinyl, and benzoxazinyl, which in each case is unsubstitutedor substituted one or more times by halogen, alkyl, hydroxy, alkoxy,alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl,amino, aminomethyl, alkylamino, aminoalkoxy, dialkylamino, hydroxyalkyl,—C(O)—NHOH, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl,cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy,trialkylsilyloxy, R⁵—L—, or combinations thereof: R⁵ is H, alkyl having1 to 8 carbon atoms, which is unsubstituted or substituted one or moretimes with halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, oxo, or combinationsthereof, alkylamino or dialkylamino wherein each alkyl portion hasindependently 1 to 8 carbon atoms, a partially unsaturatedcarbocycle-alkyl group wherein the carbocyclic portion has 5 to 14carbon atoms and the alkyl portion has 1 to 5 carbon atoms, which isunsubstituted or substituted one or more times by halogen, alkyl,alkoxy, nitro, cyano, oxo, or combinations thereof, cycloalkyl having 3to 10 carbon atoms, which is unsubstituted or substituted one or moretimes by halogen, hydroxy, oxo, cyano, alkoxy, alkyl having 1 to 4carbon atoms, or combinations thereof, cycloalkylalkyl having 4 to 16carbon atoms, which is unsubstituted or substituted in the cycloalkylportion and/or the alkyl portion one or more times by halogen, oxo,cyano, hydroxy, alkyl, alkoxy or combinations thereof, aryl having 6 to14 carbon atoms which is unsubstituted or substituted one or more timesby halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy,ethylenedioxy, trifluoromethyl, amino, aminomethyl, alkylamino,aminoalkoxy, dialkylamino, hydroxyalkyl, —C(O)—NHOH, tetrazole-5-yl,hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio,alkylsulfinyl, alkylsulfonyl, or combinations thereof arylalkyl having 7to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atomsand the alkyl portion, which is branched or unbranched, has 1 to 5carbon atoms, arylalkyl radical is unsubstituted or substituted, in thearyl portion, one or more times by halogen, trifluoromethyl, CF₃O,nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino, orcombinations thereof, and/or substituted in the alkyl portion byhalogen, cyano, methyl, or combinations thereof, a heterocyclic group,which is saturated, partially saturated or unsaturated, having 5 to 10ring atoms in which at least 1 ring atom is a N, O or S atom, which isunsubstituted or substituted one or more times by halogen, alkyl,hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy,trifluoromethyl, amino, aminomethyl, alkylamino, aminoalkoxy,dialkylamino, hydroxyalkyl, —C(O)—NHOH, tetrazole-5-yl, hydroxyalkoxy,carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl,alkylsulfonyl, phenoxy, or combinations thereof, or a heterocycle-alkylgroup, wherein the heterocyclic portion is saturated, partiallysaturated or unsaturated, and has 5 to 10 ring atoms in which at least 1ring atom is a N, O or S atom, and the alkyl portion which is branchedor unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl groupis unsubstituted or substituted one or more times in the heterocyclicportion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF₃O, nitro,oxo, amino, alkylamino, dialkylamino, or combinations thereof and/orsubstituted in the alkyl portion by halogen, cyano, or methyl orcombinations thereof; L is a single bond or a divalent aliphatic radicalhaving up to 8 carbon atoms wherein one or more —CH₂— groups are eachoptionally replaced by —O—, —S—, —SO₂—, —SO—, —NR⁶—, —SO₂NH—, —NHSO₂—,—CO—, —NR⁶CO—, —CONR⁶—, —NHCONH—, —OCONH—, —NHCOO—, —SCONH—, —SCSNH—, or—NHCSNH—; and R⁶ is H, or alkyl having 1 to 8 carbon atoms, which isbranched or unbranched and which is unsubstituted or substituted one ormore times with halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, oxo, or combinationsthereof; or a pharmaceutically acceptable salt thereof; wherein anoptically active compound can be in the form of one of its separateenantiomers or mixtures thereof, including racemic mixtures.
 28. Acompound according to formula I:

wherein R¹is: alkyl having 1 to 8 carbon atoms, which is branched orunbranched and which is substituted one or more times by halogen,cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, hydroxy, oxo, cyano, alkylhaving 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, orcombinations thereof, or a heterocyclic group, which is saturated,partially saturated or unsaturated, having 5 to 10 ring atoms in whichat least 1 ring atom is a N, O or S atom, which is unsubstituted orsubstituted one or more times by halogen, alkyl, hydroxy, alkoxy,alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl,amino, aminomethyl, alkylamino, aminoalkoxy, dialkylamino, hydroxyalkyl,—C(O)—NHOH, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl,cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, orcombinations thereof; R² is H, or alkyl having 1 to 4 carbon atoms,which is branched or unbranched and which is unsubstituted orsubstituted one or more times by halogen, cyano, and/or C₁₋₄-alkoxy, andwhere one or more —CH₂CH₂— groups are optionally replaced in each caseby —CH═CH— or —C≡C—; R³ is alkyl having 1 to 8 carbon atoms, which isbranched or unbranched and which is unsubstituted or substituted one ormore times with halogen, cyano, C₁₋₄-alkoxy, or combinations thereof, apartially unsaturated carbocycle-alkyl group wherein the carbocyclicportion has 5 to 14 carbon atoms and the alkyl portion which is branchedor unbranched has 1 to 5 carbon atoms, and which is unsubstituted orsubstituted in the carbocyclic portion one or more times by halogen,alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, and the alkylportion is optionally substituted by halogen, C₁₋₄-alkoxy, cyano orcombinations thereof, arylalkyl having 7 to 19 carbon atoms, wherein thearyl portion has 6 to 14 carbon atoms and the alkyl portion, which isbranched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical isunsubstituted or substituted, in the aryl portion, one or more times byhalogen, trifluoromethyl, CF₃O, nitro, amino, alkyl, alkoxy, alkylamino,dialkylamino and/or substituted in the alkyl portion by halogen, cyano,or methyl, or heterocyclic-alkyl group, wherein the heterocyclic portionmay be partially or fully saturated and has 5 to 10 ring atoms in whichat least 1 ring atom is a N, O or S atom, the alkyl portion, which isbranched or unbranched, has 1 to 5 carbon atoms, the heterocyclic-alkylgroup is unsubstituted or substituted one or more times in theheterocyclic portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl,CF₃O, nitro amino, alkylamino, dialkylamino, or combinations thereofand/or substituted in the alkyl portion by halogen, cyano, or methyl orcombinations thereof: R⁴ is aryl having 6 to 14 carbon atoms and whichis unsubstituted or substituted one or more times by halogen, alkyl,alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy,ethylenedioxy, trifluoromethyl, OCF₃, amino, alkylamino, aminoalkoxy,dialkylamino, hydroxyalkyl, —C(O)—NHOH, tetrazole-5-yl,2(-heterocycle)tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl,cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy,trialkylsilyloxy, R⁵—L—, or combinations thereof, or heteroaryl selectedfrom furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl,oxathiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrazinyl, oxazinyl,isoxazinyl, oxathiazinyl, oxadiazinyl, benzofuranyl, isobenzofuranyl,thionaphthenyl, isothionaphthenyl, indolyl, isoindolyl, indazolyl,benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzisothiazolyl, purinyl,benzopyranyl, qiuinolinyl, isoqiuinolinyl, cinnolinyl, qiuinazolinyl,naphthyridinyl, and benzoxazinyl, which in each case is unsubstituted orsubstituted one or more times by halogen, alkyl, hydroxy, alkoxy,alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl,amino, aminomethyl, alkylamino, aminoalkoxy, dialkylamino, hydroxyalkyl,—C(O)—NHOH, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl,cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy,trialkylsilyloxy, R⁵—L—, or combinations thereof: R⁵ is H, alkyl having1 to 8 carbon atoms, which is unsubstituted or substituted one or moretimes with halogen, C¹⁻⁴-alkyl, C¹⁻⁴-alkoxy, oxo, or combinationsthereof, alkylamino or dialkylamino wherein each alkyl portion hasindependently 1 to 8 carbon atoms, a partially unsaturatedcarbocycle-alkyl group wherein the carbocyclic portion has 5 to 14carbon atoms and the alkyl portion has 1 to 5 carbon atoms, which isunsubstituted or substituted one or more times by halogen, alkyl,alkoxy, nitro, cyano, oxo, or combinations thereof, cycloalkyl having 3to 10 carbon atoms, which is unsubstituted or substituted one or moretimes by halogen, hydroxy, oxo, cyano, alkoxy, alkyl having 1 to 4carbon atoms, or combinations thereof, cycloalkylalkyl having 4 to 16carbon atoms, which is unsubstituted or substituted in the cycloalkylportion and/or the alkyl portion one or more times by halogen, oxo,cyano, hydroxy, alkyl, alkoxy or combinations thereof, aryl having 6 to14 carbon atoms which is unsubstituted or substituted one or more timesby halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy,ethylenedioxy, trifluoromethyl, amino, aminomethyl, alkylamino,aminoalkoxy, dialkylamino, hydroxyalkyl, —C(O)—NHOH, tetrazole-5-yl,hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio,alkylsulfinyl, alkylsulfonyl, or combinations thereof arylalkyl having 7to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atomsand the alkyl portion, which is branched or unbranched, has 1 to 5carbon atoms, arylalkyl radical is unsubstituted or substituted, in thearyl portion, one or more times by halogen, trifluoromethyl, CF₃O,nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino, orcombinations thereof, and/or substituted in the alkyl portion byhalogen, cyano, methyl, or combinations thereof, a heterocyclic group,which is saturated, partially saturated or unsaturated, having 5 to 10ring atoms in which at least 1 ring atom is a N, O or S atom, which isunsubstituted or substituted one or more times by halogen, alkyl,hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy,trifluoromethyl, amino, aminomethyl, alkylamino, aminoalkoxy,dialkylamino, hydroxyalkyl, —C(O)—NHOH, tetrazole-5-yl, hydroxyalkoxy,carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl,alkylsulfonyl, phenoxy, or combinations thereof, or a heterocycle-alkylgroup, wherein the heterocyclic portion is saturated, partiallysaturated or unsaturated, and has 5 to 10 ring atoms in which at least 1ring atom is a N, O or S atom, and the alkyl portion which is branchedor unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl groupis unsubstituted or substituted one or more times in the heterocyclicportion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF₃O, nitro,oxo, amino, alkylamino, dialkylamino, or combinations thereof and/orsubstituted in the alkyl portion by halogen, cyano, or methyl orcombinations thereof; L is a single bond or a divalent aliphatic radicalhaving up to 8 carbon atoms wherein one or more —CH₂— groups are eachoptionally replaced by —O—, —S—, —SO₂—, —SO—, —NR⁶—, —SO₂NH—, —NHSO₂—,—CO—, —NR⁶CO—, —CONR⁶—, —NHCONH—, —OCONH—, —NHCOO—,—SCONH—, —SCSNH—, or—NHCSNH—; and R⁶ is H, or alkyl having 1 to 8 carbon atoms, which isbranched or unbranched and which is unsubstituted or substituted one ormore times with halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, oxo, or combinationsthereof; or a pharmaceutically acceptable salt thereof; wherein anoptically active compound can be in the form of one of its separateenantiomers or mixtures thereof, including racemic mixtures.
 29. Acompound according to claim 28, wherein R¹ is: alkyl having 1 to 8carbon atoms which is substituted one or more times by halogen, orcycloalkyl having 3 to 10 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, hydroxy, oxo, cyano, alkylhaving 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, orcombinations thereof.
 30. A compound according to claim 29, wherein R¹is cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, hydroxy, oxo, cyano, alkylhaving 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, orcombinations thereof.
 31. A compound according to claim 30, wherein R¹is cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, hydroxy, oxo, cyano, alkylhaving 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, orcombinations thereof.
 32. A compound according to claim 31, wherein R¹is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. 33.A compound according to claim 32, wherein R¹ is cyclopentyl.
 34. Acompound of claim 2, wherein R⁴ is pyridyl which is unsubstituted orsubstituted one or more times by halogen, alkyl, hydroxy, alkoxy,alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl,amino, aminomethyl, alkylamino, aminoalkoxy, dialkylamino, hydroxyalkyl,—C(O)—NHOH, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl,hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio,alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy, R⁵—L—, orcombinations thereof.
 35. A compound according to claim 28, wherein R³is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl,pentyl, hexyl, heptyl, octyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-,1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,ethylmethylpropyl, trimethylpropyl, methylhexyl, dimethylpentyl,ethylpentyl, ethylmethylbutyl, dimethylbutyl, or an alkyl having 1 to 8carbon atoms, which is branched or unbranched and which is substitutedone or more times with halogen.